- A facile synthesis of (2R,3S)-1-amino-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutane; A useful component block of HIV protease inhibitor
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(S)-3-tert-Butoxycarbonylamino-1-nitro-2-oxo-4-phenylbutane 4 was converted to (2R,3S)-1-amino-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutane 5a by a catalytic hydrogenation, or NaBH4-TiCl4 reduction followed by hydrogenation in favorable diastereoselectivity, a component of the HIV protease inhibitor VX-478.
- Yuasa, Yoko,Yuasa, Yoshifumi,Tsuruta, Haruki
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Read Online
- Synthesis and biological evaluation in vitro and in mammalian cells of new heteroaryl carboxyamides as HIV-protease inhibitors
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New heteroaryl HIV-protease inhibitors bearing a carboxyamide spacer were synthesized in few steps and high yield, from commercially available homochiral epoxides. Different substitution patterns were introduced onto a given isopropanoyl-sulfonamide core modifying the type of heteroarene and the central core, with the presence of either H or benzyl group. Their in vitro inhibition activity against recombinant protease showed a general beneficial effect of carboxyamide moiety, the IC50 values ranging between 1 and 15nM. In particular benzofuryl derivatives showed IC50 values among the best for such structurally simple inhibitors. Docking analysis allowed to identify the favorable situation of such benzofuryl derivatives in terms of number of interactions in the active site, supporting the experimental results on activity.The inhibition activity of such molecules has been also evaluated in HEK293 cells expressing the protease fused to green fluorescent protein, by western blotting analysis, fluorescence microscopy and cytofluorimetry.
- Funicello,Chiummiento,Tramutola,Armentano,Bisaccia,Miglionico,Milella,Benedetti,Berti,Lupattelli
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Read Online
- An improved and robust scale-up process aided with identification and control of critical process impurities in darunavir ethanolate
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A robust and safe industrial process, including five isolations and drying steps for widely prescribed anti-HIV (protease inhibitor) drug darunavir ethanolate 2, has been developed. A salient feature of this process is the development of procedures enabling the efficient synthesis of multi-kilogram quantity of darunavir ethanolate, and process demonstrations through plant scale preparation are offered where darunavir molecule has been prepared with overall > 70% chemical yield and > 99.8% purity without involving any purification procedure(s), with all possible process impurities below than the desired limit (not more than 0.08%) were isolated, synthesized and characterized. The developed process is entirely robust, very efficient and demonstrated up to kilograms scale.
- Girigani, Sathyanarayana,Singh, Harnam,Kola, Sankar Rao,Dayanand Yelmeli, Vijayalaxmi,Regula, Venu Gopal,Shah, Sakshi,Jain, Neelu,Kumar, Pramod
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Read Online
- Design and evaluation of novel piperidine HIV-1 protease inhibitors with potency against DRV-resistant variants
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A novel class of HIV-1 protease inhibitors with flexible piperidine as the P2 ligand was designed with the aim of improving extensive interactions with the active subsites. Many inhibitors exhibited good to excellent inhibitory effect on enzymatic activity and viral infectivity. In particular, inhibitor 3a with (R)-piperidine-3-carboxamide as the P2 ligand and 4-methoxybenzenesulfonamide as the P2’ ligand showed an enzyme Ki value of 29 pM and antiviral IC50 value of 0.13 nM, more than six-fold enhancement of activity compared to DRV. Furthermore, there was no significant change in potency against DRV-resistant mutations and HIV-1NL4?3 variant for 3a. Besides, inhibitor 3a exhibited potent antiviral activity against subtype C variants with low nanomole EC50 values. In addition, the molecular modeling revealed important hydrogen bonds and other favorable van der Waals interactions with the backbone atoms of the protease and provided insight for designing and optimizing more potent HIV-1 protease inhibitors.
- Zhu, Mei,Zhou, Huiyu,Ma, Ling,Dong, Biao,Zhou, Jinming,Zhang, Guoning,Wang, Minghua,Wang, Juxian,Cen, Shan,Wang, Yucheng
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- Nitrogen-containing heterocyclic amino derivative, preparation method thereof and anti-HIV-1 medicine
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The invention provides a nitrogen-containing heterocyclic ring amino derivative, a preparation method thereof and an anti-HIV-1 medicine, and belongs to the technical field of medicine application. The nitrogen-containing heterocyclic ring amino derivative provided by the invention can interfere with the process of hydrolyzing Gap and Gap-Pol precursor polyprotein by HIV-1 protease, and has high HIV-1 protease inhibitory activity; meanwhile, the nitrogen-containing heterocyclic ring amino derivative provided by the invention has remarkable inhibitory activity on wild type anti-HIV-1 medicine strains and high anti-DRV-medicine strains, has low cytotoxicity, and has a good application prospect as an anti-AIDS medicine.
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Paragraph 0368-0375; 0394-0398; 0409-0413; 0422-0426;...
(2021/08/21)
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- Design and biological evaluation of cinnamic and phenylpropionic amide derivatives as novel dual inhibitors of HIV-1 protease and reverse transcriptase
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Upon the basis of both possible ligand-binding site interactions and the uniformity of key residues in active sites, a novel class of HIV-1 PR/RT dual inhibitors was designed and evaluated. Cinnamic acids or phenylpropionic acids with more flexible chain and smaller steric hindrance were introduced into the inhibitors, giving rise to significant improvement in HIV-1 RT inhibitory activity by one or two orders of magnitude, with comparable or even improved potency against PR at the same time, compared with coumarin anologues in our previous studies. Among these inhibitors, 38d displayed a 19-fold improvement in anti-PR activity with IC50 value of 0.081 nM compared to the control DRV. In addition, inhibitor 38c exhibited an excellent anti-RT IC50 value of 0.43 μM, only a 4.7-fold less potent activity than the control EFV. More significantly, the disparate ratio between HIV-1 PR and RT inhibition became more reasonable with ratio of 1: 10.4, just as 37b. Furthermore, the assays on HIV-1 late stage and early stage supported the rationality of designing dual inhibitors. The SAR data as well as molecular modeling studies provided new insight for further optimization of more potent HIV-1 PR/RT dual inhibitors.
- Zhu, Mei,Shan, Qi,Ma, Ling,Wen, Jiajia,Dong, Biao,Zhang, Guoning,Wang, Minghua,Wang, Juxian,Zhou, Jinming,Cen, Shan,Wang, Yucheng
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- Novel HIV-1 Protease Inhibitors with Morpholine as the P2 Ligand to Enhance Activity against DRV-Resistant Variants
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Flexible heterocyclic moieties as the P2 ligands of HIV-1 protease inhibitors may be adapted to the minimally distorted active site of mutations easily and enhance activity against DRV-resistant HIV-1 variants. Herein, the design, synthesis, and biological evaluation of a new series of inhibitors containing morpholine derivatives as the P2 ligands were described, among which, carbamate inhibitor 23a and carbamido inhibitor 27a exhibited almost 4- and 2-fold superior activity with enzyme Ki of 0.092 nM and 0.21 nM, as well as antiviral IC50 values of 0.41 nM and 0.95 nM, respectively, compared to DRV. Besides, they exhibited excellent activity with inhibition of 94percent and 91percent, respectively. Furthermore, they also showed appreciable antiviral activity against DRV-resistant HIV-1 variants.
- Cen, Shan,Dong, Biao,Dou, Yue,Ma, Ling,Wang, Juxian,Wang, Yucheng,Zhang, Fan,Zhang, Guoning,Zhou, Jinming,Zhu, Mei
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p. 1196 - 1204
(2020/07/04)
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- Rational design and Structure?Activity relationship of coumarin derivatives effective on HIV-1 protease and partially on HIV-1 reverse transcriptase
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Since dual inhibitors may yield lower toxicity and reduce the likelihood of drug resistance, as well as inhibitors of HIV-1 PR and RT constitute the core of chemotherapy for AIDS treatment, we herein designed and synthesized new coumarin derivatives characterized by various linkers that exhibited excellent potency against PR and a weak inhibition of RT. Among which, compounds 6f and 7c inhibited PR with IC50 values of 15.5 and 62.1 nM, respectively, and weakly affected also RT with IC50 values of 241.8 and 188.7 μM, respectively, showing the possibility in the future of developing dual HIV-1 PR/RT inhibitors. Creative stimulation for further research of more potent dual HIV-1 inhibitors was got according to the molecular docking studies.
- Zhu, Mei,Ma, Ling,Wen, Jiajia,Dong, Biao,Wang, Yujia,Wang, Zhen,Zhou, Jinming,Zhang, Guoning,Wang, Juxian,Guo, Ying,Liang, Chen,Cen, Shan,Wang, Yucheng
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- Preliminary SAR and biological evaluation of potent HIV-1 protease inhibitors with pyrimidine bases as novel P2 ligands to enhance activity against DRV-resistant HIV-1 variants
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Introducing pyrimidine bases, the basic components of nucleic acid, to P2 ligands might enhance the potency of Human Immunodeficiency Virus-1 (HIV-1) protease inhibitors because of the carbonyl and amino groups promoting the formation of extensive hydrogen bonding interactions. In this work, we provide evidence that inhibitor 10e, with N-2-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetamide as the P2 ligand and a 4-methoxylphenylsulfonamide as the P2′ ligand, displayed remarkable enzyme inhibitory and antiviral activity, with the IC50 2.53 nM in vitro and a promising inhibition ratio with 68% against wild-type HIV-1 in vivo, with low cytotoxicity. This inhibitor also exhibited appreciable antiviral activity against DRV-resistant HIV-1 variants, which was of great value for further study.
- Zhu, Mei,Ma, Ling,Zhou, Huiyu,Dong, Biao,Wang, Yujia,Wang, Zhen,Zhou, Jinming,Zhang, Guoning,Wang, Juxian,Liang, Chen,Cen, Shan,Wang, Yucheng
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- New heteroaryl carbamates: Synthesis and biological screening in vitro and in mammalian cells of wild-type and mutant HIV-protease inhibitors
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New heteroaryl HIV-protease inhibitors bearing a carbamoyl spacer were synthesized in few steps and high yield, from commercially available homochiral epoxides. Different substitution patterns were introduced onto a given isopropanoyl-sulfonamide core that can have either H or benzyl group. The in vitro inhibition activity against recombinant protease showed a general beneficial effect of both carbamoyl moiety and the benzyl group, ranging the IC50 values between 11 and 0.6 nM. In particular, benzofuryl and indolyl derivatives showed IC50 values among the best for such structurally simple inhibitors. Docking analysis allowed to identify the favorable situation of such derivatives in terms of number of interactions in the active site, supporting the experimental results. The inhibition activity was also confirmed in HEK293 mammalian cells and was maintained against protease mutants. Furthermore, the metabolic stability was comparable with that of the commercially available inhibitors.
- Tramutola, Francesco,Armentano, Maria Francesca,Berti, Federico,Chiummiento, Lucia,Lupattelli, Paolo,D'Orsi, Rosarita,Miglionico, Rocchina,Milella, Luigi,Bisaccia, Faustino,Funicello, Maria
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p. 1863 - 1870
(2019/03/27)
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- HIV-1 Protease Inhibitors Incorporating Stereochemically Defined P2′ Ligands to Optimize Hydrogen Bonding in the Substrate Envelope
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A structure-guided design strategy was used to improve the resistance profile of HIV-1 protease inhibitors by optimizing hydrogen bonding and van der Waals interactions with the protease while staying within the substrate envelope. Stereoisomers of 4-(1-hydroxyethyl)benzene and 4-(1,2-dihydroxyethyl)benzene moieties were explored as P2′ ligands providing pairs of diastereoisomers epimeric at P2′, which exhibited distinct potency profiles depending on the configuration of the hydroxyl group and size of the P1′ group. While compounds with the 4-(1-hydroxyethyl)benzene P2′ moiety maintained excellent antiviral potency against a panel of multidrug-resistant HIV-1 strains, analogues with the polar 4-(1,2-dihydroxyethyl)benzene moiety were less potent, and only the (R)-epimer incorporating a larger 2-ethylbutyl P1′ group showed improved potency. Crystal structures of protease-inhibitor complexes revealed strong hydrogen bonding interactions of both (R)- and (S)-stereoisomers of the hydroxyethyl group with Asp30′. Notably, the (R)-dihydroxyethyl group was involved in a unique pattern of direct hydrogen bonding interactions with the backbone amides of Asp29′ and Asp30′. The SAR data and analysis of crystal structures provide insights for optimizing these promising HIV-1 protease inhibitors.
- Rusere, Linah N.,Lockbaum, Gordon J.,Lee, Sook-Kyung,Henes, Mina,Kosovrasti, Klajdi,Spielvogel, Ean,Nalivaika, Ellen A.,Swanstrom, Ronald,Yilmaz, Nese Kurt,Schiffer, Celia A.,Ali, Akbar
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supporting information
p. 8062 - 8079
(2019/09/09)
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- Synthesis and biological evaluation of new HIV-1 protease inhibitors with purine bases as P2-ligands
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Introducing purine bases to P2-ligands might enhance the potency of Human Immunodeficiency Virus-1 (HIV-1) protease inhibitory because of the carbonyl and NH groups promoting the formation of extensive H-bonding interactions. In this work, thirty-three compounds are synthesized and evaluated, among which inhibitors 16a, 16f and 16j containing N-2-(6-substituted-9H-purin-9-yl)acetamide as the P2-ligands along with 4-methoxylphenylsulfonamide as the P2′-ligand, display potent inhibitory effect on the activity of HIV-1 protease with IC50 43 nM, 42 nM and 68 nM in vitro, respectively.
- Zhu, Mei,Dong, Biao,Zhang, Guo-Ning,Wang, Ju-Xian,Cen, Shan,Wang, Yu-Cheng
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p. 1541 - 1545
(2019/04/25)
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- Design, synthesis and biological evaluation of novel HIV-1 protease inhibitors with pentacyclic triterpenoids as P2-ligands
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The design, synthesis and SAR study of a new series of HIV-1 protease inhibitors with pentacyclic triterpenoids as P2 ligands and phenylsulfonamide as P2′ ligands were discussed. These compounds exhibited micromolar inhibitory potency, among which compound T1c displayed HIV-1 protease inhibition with IC50 values of 0.12 μM, which was 67 times the inhibitory activity of its raw material Ursolic acid (8.0 μM).
- Zhu, Mei,Du, Xiao-Nan,Li, Yun-Ge,Zhang, Guo-Ning,Wang, Ju-Xian,Wang, Yu-Cheng
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p. 357 - 361
(2019/01/04)
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- A NOVEL PROCESS FOR THE PREPARATION OF HIV PROTEASE INHIBITOR AND INTERMEDIATES THEREOF
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The present invention relates to process for the preparation of Darunavir or a solvate thereof of Formula (I) using a novel intermediate (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (2S,3R)-4-(4-(1,3-dioxoisoindolin-2-yl)-N-isobutylphenylsulfonamido)-3 -hydroxy- 1 -phenylbutan-2- ylcarbamate Compound of formula (II): The present invention also relates to the process for the preparation of novel intermediates (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (2S,3R)-4-(4-(l,3-dioxo iso indolin-2-yl)-N-isobutylphenylsulfonamido)-3 -hydroxy-1-phenylbutan-2-ylcarbamate Compound of formula (II). Darunavir or its solvate of formula (I) are useful therapeutic agent and used in treatment of antiviral diseases.
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Page/Page column 17-18
(2018/02/16)
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- RT/PR dual-target HIV inhibitor, preparation method and applications thereof
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The invention discloses an RT/PR dual-target HIV inhibitor, a preparation method and applications thereof. According to the present invention, the RT/PR dual-target HIV inhibitor is prepared from a compound represented by a formula 1, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula 1 has obvious inhibition activity on HIV reverse transcriptase and HIVprotease; and the toxicity study results show that the compound has good drug-forming property, such that the compound as the anti-acquired immunodeficiency syndrome drug has good application prospects. The formula I is defined in the specification.
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Paragraph 0058; 0060; 0061
(2018/09/11)
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- Amide derivative or pharmaceutically acceptable salt thereof and preparation method and application thereof
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The invention provides an amide derivative or a pharmaceutically acceptable salt thereof with the structure as shown in formula I. A compound or the pharmaceutically acceptable salt thereof has significant activity in inhibiting HIV protease and reverse transcriptase; toxicity study shows that the compound or the pharmaceutically acceptable salt thereof has better druggability, and the compound has better application prospect in using as anti-Aids drugs. According to experimental data, the compound has inhibiting activity both on HIV-1 protease and HIV-1 reverse transcriptase and has lower cytotoxicity. The compound or the pharmaceutically acceptable salt thereof is expected to be a double-target inhibitor which can inhibit the HIV protease and the reverse transcriptase.
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Paragraph 0234; 0235; 0236; 0237; 0238
(2018/10/19)
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- Nucleic acid base compound or medically acceptable salt thereof and preparation method and application of compound or salt thereof
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The invention provides a nucleic acid base compound or a medically acceptable salt thereof. The compound or the medically acceptable salt thereof has the obvious inhibitory HIV protease and/or reversetranscriptase activity; toxicity studies show that the compound has the good druggability, it is indicated that the compound has a good application prospect by serving as an anti-AIDs drug. Accordingto experimental data, the compound has inhibitory activity on HIV-1 protease and HIV-1 reverse transcriptase, and low cytotoxicity exits. The nucleic acid base compound or the medically acceptable salt thereof is expected to become a double-target inhibitor inhibiting the HIV protease and the reverse transcriptase simultaneously.
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Paragraph 0164; 0166
(2018/10/19)
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- Intermediate reaches reed that Wei new synthetic process of the
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The invention provides a novel synthesis process of Darunavir intermediate, N-tertbutyloxycarbonyl-L-phenylalanine is used as a raw material, esterification, condensation, reduction, hydrogenation and reduction amination, and other reactions are carried out for preparing the key intermediate of Darunavir: (2R,3S)-3-(tert-butyloxycarbonyl)amino-1-[(2-methyl propyl)amino]-4-phenyl-2-butanol. The new synthesis process of Darunavir intermediate has the advantages of mild reaction condition, simple operation, and high reaction selectivity and yield, and the process is suitable for industrial production.
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- Design and synthesis of potent HIV-1 protease inhibitors with (S)-tetrahydrofuran-tertiary amine-acetamide as P2?ligand: Structure?activity studies and biological evaluation
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The design, synthesis, and SAR study of a new series of HIV-1 protease inhibitors incorporating stereochemically defined tetrahydrofuran-tertiary amine-acetamide P2-ligand are described. Various substituent effects on the tertiary amine P2-ligand and phenylsulfonamide P2′-ligand were investigated to maximize the ligand-binding site interactions in the protease active site. Most of inhibitors displayed low nanomolar to subnanomolar inhibitory potency. Inhibitor 20e containing N-(S-tetrahydrofuran)-N-(2-methoxyethyl)acetamide as P2-ligand along with 4-methoxylphenylsulfonamide as P2′-ligand displayed the most potent enzyme inhibitory activity (IC50 = 0.35 nM) and remarkably low cytotoxicity (CC50 = 305 μM).
- Bai, Xiaoguang,Yang, Zhiheng,Zhu, Mei,Dong, Biao,Zhou, Lei,Zhang, Guoning,Wang, Juxian,Wang, Yucheng
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- 4-amino-N-[ (2R, 3S) - 3-amino-2-hydroxy-4-phenyl-butyl]-N- isobutyl-benzene sulfonaide preparation method
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The invention discloses a method for preparing 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-benzene butyl]-N-isobutyl benzsulfamide. The method comprises the following steps: S1: enabling L-phenylalanine and diazomethane to react to obtain a diazo methyl ketone intermediate product, and enabling the diazo methyl ketone intermediate product and haloid acid to react to obtain a compound A; S2, conducting carbonyl deoxidation on the compound A to obtain a compound B; S3, under the existence of iso-butylamine, conducting cyclization reaction and ring-opening reaction on the compound B in sequence to obtain a compound C; S4, enabling the compound C and nitrobenzenesulfonyl chloride to react to obtain a compound D; S5, conducting nitro reduction on the compound D to obtain the 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-benzene butyl]-N-isobutyl benzsulfamide. The method is simple in course, low in cost, mild in condition, and higher in intermediate product stability, and is beneficial for industrial application.
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- A Concise One-Pot Organo- and Biocatalyzed Preparation of Enantiopure Hexahydrofuro[2,3-b]furan-3-ol: An Approach to the Synthesis of HIV Protease Inhibitors
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A simple and efficient one-pot synthesis of enantiopure hexahydrofuro[2,3-b]furan-3-ol, a crucial component of HIV-1 protease inhibitors, was developed. The one-pot process involves an organocatalytic condensation followed by an enzymatic optical resolution. The condensation of 1,2-dihydrofuran and glycolaldehyde was achieved using Schreiner's thiourea catalyst (1 mol-%). A subsequent lipase-catalyzed kinetic resolution gave the target alcohol with >99 % ee. To demonstrate the practicality of this method, Darunavir, an HIV-1 protease inhibitor used to treat multi-drug-resistant HIV, was synthesized.
- Kanemitsu, Takuya,Inoue, Mizuho,Yoshimura, Nono,Yoneyama, Kazutoshi,Watarai, Rie,Miyazaki, Michiko,Odanaka, Yuki,Nagata, Kazuhiro,Itoh, Takashi
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p. 1874 - 1880
(2016/05/09)
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- PROCESS FOR THE PREPARATION OF DARUNAVIR
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The present invention provides a cost effective and industrially feasible process for preparation of Darunavir (I). Also described is the novel salt of intermediate 4-Amino-N- ((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzene sulfonamide acid salt (VIII) and its use in the preparation of Darunavir. Formula (I) and (VII).
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(2016/12/22)
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- NOVEL SOLVATES OF DARUNAVIR
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The present invention relates to novel solvates of Darunavir of Formula I.
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Paragraph 0095; 0096; 0097
(2015/05/26)
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- Crystalline Darunavir
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The present invention relates to a non-solvated crystalline Darunavir, process for its preparation and pharmaceutical composition comprising it. The present invention also relates to a process for the preparation of amorphous Darunavir from a non-solvated crystalline Darunavir.
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- PROCESS FOR THE PREPARATION OF SULFONAMIDES USEFUL AS RETROVIRAL PROTEASE INHIBITORS
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The present invention relates to a process for the preparation of sulfonamides useful as retroviral protease inhibitors.
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Page/Page column 29; 30
(2013/03/26)
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- NOVEL SOLVATES OF DARUNAVIR
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The present invention relates to novel solvates of Darunavir of Formula (I).
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Page/Page column 14; 16
(2013/07/31)
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- CRYSTALLINE DARUNAVIR
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The present invention relates to a non-solvated crystalline Darunavir, process for its preparation and pharmaceutical composition comprising it. The present invention also relates to a process for the preparation of amorphous Darunavir from a non-solvated crystalline Darunavir.
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- PROCESS FOR THE PREPARATION OF DARUNAVIR
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A process for the preparation of Darunavir comprises the reacting of 4-amino-N-(2R,3S) (3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-benzenesulfonamide with (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol derivative in N-methyl-2-pyrrolidinone and isolating the resulting Darunavir. The process yields Darunavir with a very low level of the difuranyl impurity.
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Page/Page column 9
(2012/10/08)
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- PREPARATION OF FOSAMPRENAVIR CALCIUM
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Process for preparation of fosamprenavir and its intermediate salts using novel phthalimide intermediates.
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Page/Page column 6
(2011/10/04)
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- NOVEL CARBOXAMIDE DERIVATIVES AS HIV INHIBITORS
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The present invention relates to carboxamide derivatives of Formula (I), where B1, B2, X, L, n, R, R1, R2, Z1, Z2, Rx and Ry are as defined in the claims, as compounds and compositions for inhibiting Human Immunodeficiency Virus (HIV) and process for making the compounds.
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Page/Page column 39
(2011/06/19)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF DARUNAVIR
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The present invention relates to the process for the preparation of Darunavir, solvates or pharmaceutically acceptable salts with improved yield and quality having the difuranyl impurity of formula (1) less than 0.1%. The present invention also relates to provide processes for the preparation of amorphous Darunavir. Further, the present invention also relates to pharmaceutical composition of crystalline or amorphous Darunavir, solvates or pharmaceutically acceptable salts having the difuranyl impurity of formula (1) less than 0.1%.
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Page/Page column 18
(2011/05/06)
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- Synthesis of deuterium-labelled fosamprenavir calcium
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This study describes the synthesis of deuterium-labelled fosamprenavir calcium. The stable isotopic-labelled compound was prepared starting from L-phenylalanine in 18 steps with a 9% overall yield. Copyright
- Shi, Lei,Chen, Liping,Chen, Ryan,Chen, Liqin
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p. 148 - 152
(2011/07/31)
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- AMIDE COMPOUNDS AS BOOSTERS OF ANTIVIRALS
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The present invention relates to compounds that have CYP450 inhibiting properties and are therefore useful as boosters of certain drugs, i.e. they are able to increase at least one of the pharmacokinetic variables of certain drugs when co-administered. The invention further provides the use of said compounds as improvers of the bioavailability of certain drugs. Methods for the preparation of the compounds of the invention and pharmaceutical compositions are also provided.
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Page/Page column 21-22
(2010/12/29)
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- PROTEASE INHIBITORS
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Compounds useful as protease inhibitors are provided, as are methods of use and preparation of such compounds and compositions containing such compounds. In one embodiment, the compounds are useful for inhibiting HIV protease enzymes, and are therefore useful in slowing the proliferation of HIV.
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Page/Page column 108
(2010/08/04)
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- Structure-based design, synthesis, and structure-activity relationship studies of HIV-1 protease inhibitors incorporating phenyloxazolidinones
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A series of new HIV-1 protease inhibitors with the hydroxyethylamine core and different phenyloxazolidinone P2 ligands were designed and synthesized. Variation of phenyl substitutions at the P2 and P2' moieties significantly affected the binding affinity and antiviral potency of the inhibitors. In general, compounds with 2- and 4-substituted phenyloxazolidinones at P2 exhibited lower binding affinities than 3-substituted analogues. Crystal structure analyses of ligand-enzyme complexes revealed different binding modes for 2- and 3-substituted P2 moieties in the protease S2 binding pocket, which may explain their different binding affinities. Several compounds with 3-substituted P2 moieties demonstrated picomolar binding affinity and low nanomolar antiviral potency against patient-derived viruses from HIV-1 clades A, B, and C, and most retained potency against drug-resistant viruses. Further optimization of these compounds using structure-based design may lead to the development of novel protease inhibitors with improved activity against drug-resistant strains of HIV-1.
- Ali, Akbar,Reddy, G. S. Kiran Kumar,Nalam, Madhavi N. L.,Anjum, Saima Ghafoor,Cao, Hong,Schiffer, Celia A.,Rana, Tariq M.
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experimental part
p. 7699 - 7708
(2010/12/30)
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- NEW AMIDE COMPOUNDS AS BOOSTERS OF ANTIVIRALS
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The present invention relates to compounds that have CYP450 inhibiting properties and are therefore useful as boosters of certain drugs, i.e. they are able to increase at least one of the pharmacokinetic variables of certain drugs when co-administered. The invention further provides the use of said compounds as improvers of the bioavailability of certain drugs. Methods for the preparation of the compounds of the invention and pharmaceutical compositions comprising these compounds are also provided.
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Page/Page column 32
(2010/04/28)
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- Additivity in the analysis and design of HIV protease inhibitors
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We explore the applicability of an additive treatment of substituent effects to the analysis and design of HIV protease inhibitors. Affinity data for a set of inhibitors with a common chemical framework were analyzed to provide estimates of the free energy contribution of each chemical substituent. These estimates were then used to design new inhibitors whose high affinities were confirmed by synthesis and experimental testing. Derivations of additive models by least-squares and ridge-regression methods were found to yield statistically similar results. The additivity approach was also compared with standard molecular descriptor-based QSAR; the latter was not found to provide superior predictions. Crystallographic studies of HIV protease-inhibitor complexes help explain the perhaps surprisingly high degree of substituent additivity in this system, and allow some of the additivity coefficients to be rationalized on a structural basis.
- Jorissen, Robert N.,Kiran Kumar Reddy,Ali, Akbar,Altman, Michael D.,Chellappan, Sripriya,Anjum, Saima G.,Tidor, Bruce,Schiffer, Celia A.,Rana, Tariq M.,Gilson, Michael K.
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body text
p. 737 - 754
(2009/12/07)
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- HIV-1 protease inhibitors from inverse design in the substrate envelope exhibit subnanomolar binding to drug-resistant variants
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The acquisition of drug-resistant mutations by infectious pathogens remains a pressing health concern, and the development of strategies to combat this threat is a priority. Here we have applied a general strategy, inverse design using the substrate envelope, to develop inhibitors of HIV-1 protease. Structure-based computation was used to design inhibitors predicted to stay within a consensus substrate volume in the binding site. Two rounds of design, synthesis, experimental testing, and structural analysis were carried out, resulting in a total of 51 compounds. Improvements in design methodology led to a roughly 1000-fold affinity enhancement to a wild-type protease for the best binders, from a Ki of 30-50 nM in round one to below 100 pM in round two. Crystal structures of a subset of complexes revealed a binding mode similar to each design that respected the substrate envelope in nearly all cases. All four best binders from round one exhibited broad specificity against a clinically relevant panel of drug-resistant HIV-1 protease variants, losing no more than 6-13-fold affinity relative to wild type. Testing a subset of second-round compounds against the panel of resistant variants revealed three classes of inhibitors: robust binders (maximum affinity loss of 14-16-fold), moderate binders (35-80-fold), and susceptible binders (greater than 100-fold). Although for especially high-affinity inhibitors additional factors may also be important, overall, these results suggest that designing inhibitors using the substrate envelope may be a useful strategy in the development of therapeutics with low susceptibility to resistance.
- Altman, Michael D.,Ali, Akbar,Reddy, G. S. Kiran Kumar,Nalam, Madhavi N. L.,Anjum, Saima Ghafoor,Cao, Hong,Chellappan, Sripriya,Kairys, Visvaldas,Fernandes, Miguel X.,Gilson, Michael K.,Schiffer, Celia A.,Rana, Tariq M.,Tidor, Bruce
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p. 6099 - 6113
(2008/09/21)
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- HIV-1 PROTEASE INHIBITORS
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Described are novel protease inhibitors and methods for using said protease inhibitors in the treatment of human immunodeficiency virus (HIV) infection.
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Page/Page column 5; 93; 22/39
(2008/12/04)
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- METHOD AND COMPOSITIONS FOR TREATING HIV INFECTIONS
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Described herein are compounds and compositions that are useful in the treatment of HIV, AIDS, and AIDS-related diseases. In addition, compounds are described herein that are capable of inhibiting the dimerization of HIV proteases.
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Page/Page column 26-28
(2008/12/08)
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- SUBSTITUTED AMINOPHENYLSULFONAMIDE COMPOUNDS AS HIV PROTEASE INHIBITOR
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The present invention concerns substituted aminophenylsulfonamide compounds, their use as protease inhibitors, in particular as broad-spectrum HIV protease inhibitors, processes for their preparation as well as pharmaceutical compositions and diagnostic kits comprising them. The present invention also concerns combinations of the present substituted aminophenylsulfonamide compounds with another anti-retroviral agent. It further relates to their use in assays as reference compounds or as reagents.
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Page/Page column 18-19
(2008/06/13)
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- AMINOPHENYLSULFONAMIDE DERIVATIVES AS HIV PROTEASE INHIBITOR
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The present invention concerns substituted aminophenylsulfonamide compounds and derivatives, their use as protease inhibitors, in particular as broadspectrum HIV protease inhibitors, processes for their preparation as well as pharmaceutical compositions and diagnostic kits comprising them. The present invention also concerns combinations of the present substituted aminophenylsulfonamide compounds and derivatives with another anti-retroviral agent. It further relates to their use in assays as reference compounds or as reagents.
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Page/Page column 17; 19
(2008/06/13)
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- Synthesis, antiviral activity, and pharmacokinetic evaluation of P3 pyridylmethyl analogs of oximinoarylsulfonyl HIV-1 protease inhibitors
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As a continuation of the recently communicated discovery of oximinoarylsulfonamides as potent inhibitors of HIV-1 aspartyl protease, compounds bearing pyridylmethyl substituents at P3 were designed and synthesized. Potent analogs in this series provided low single-digit nanomolar EC50 values against both wild-type HIV and resistant mutant virus (A17), attenuated some 3- to 12-fold in the presence of 50% human serum. Pharmacokinetic results for compounds in this series showed good to excellent exposure when co-administered orally with an equal amount of ritonavir (5 mg/kg each) in the rat, with average AUC >8 μg h/mL. Similar dosing in dog resulted in significantly lower plasma levels (average AUC i = 2.4 nM).
- Randolph, John T.,Huang, Peggy P.,Flosi, William J.,DeGoey, David,Klein, Larry L.,Yeung, Clinton M.,Flentge, Charles,Sun, Mingua,Zhao, Chen,Dekhtyar, Tatyana,Mo, Hongmei,Colletti, Lynn,Kati, Warren,Marsh, Kennan C.,Molla, Akhteruzzaman,Kempf, Dale J.
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p. 4035 - 4046
(2007/10/03)
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- Structure-based design of novel HIV-1 protease inhibitors to combat drug resistance
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Structure-based design and synthesis of novel HIV protease inhibitors are described. The inhibitors are designed specifically to interact with the backbone of HIV protease active site to combat drug resistance. Inhibitor 3 has exhibited exceedingly potent enzyme inhibitory and antiviral potency. Furthermore, this inhibitor maintains impressive potency against a wide spectrum of HIV including a variety of multi-PI-resistant clinical strains. The inhibitors incorporated a stereochemically defined 5-hexahydrocyclopenta[b] furanyl urethane as the P2-ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. Optically active (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[e]furan was prepared by an enzymatic asymmetrization of meso-diacetate with acetyl cholinesterase, radical cyclization, and Lewis acid-catalyzed anomeric reduction as the key steps. A protein-ligand X-ray crystal structure of inhibitor 3-bound HIV-1 protease (1.35 ? resolution) revealed extensive interactions in the HIV protease active site including strong hydrogen bonding interactions with the backbone. This design strategy may lead to novel inhibitors that can combat drug resistance.
- Ghosh, Arun K.,Sridhar, Perali Ramu,Leshchenko, Sofiya,Hussain, Azhar K.,Li, Jianfeng,Kovalevsky, Andrey Yu.,Walters, D. Eric,Wedekind, Joseph E.,Grum-Tokars, Valerie,Das, Debananda,Koh, Yasuhiro,Maeda, Kenji,Gatanaga, Hiroyuki,Weber, Irene T.,Mitsuya, Hiroaki
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p. 5252 - 5261
(2008/02/11)
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- Epoxide opening in water and screening in situ for rapid discovery of enzyme inhibitors in microtiter plates
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A method utilizing the strategy of epoxide opening by amine with water as co-solvent and screening in situ was developed for rapid discovery of protein inhibitors. Using this approach, HIV protease inhibitors with novel P1′ residues were identified in our study. This strategy should be applicable for the efficient assembly of diverse compound collections for inhibitors' discovery and optimization in other systems.
- Liang, Fu-Sen,Brik, Ashraf,Lin, Ying-Chuan,Elder, John H.,Wong, Chi-Huey
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p. 1058 - 1062
(2007/10/03)
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- Design and synthesis of novel HIV-1 protease inhibitors incorporating oxyindoles as the P′2-ligands
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A series of novel oxyindole-derived HIV-1 protease inhibitors were designed and synthesized based upon our X-ray crystal structure of inhibitor 2 (TMC-114) bound to HIV-1 protease. The effects of substituents, spirocyclic rings, and ring sizes have been investigated. A number of inhibitors exhibited low nanomolar inhibitory potencies against HIV protease.
- Ghosh, Arun K.,Schiltz, Gary,Perali, Ramu Sridhar,Leshchenko, Sofiya,Kay, Stephanie,Walters, D. Eric,Koh, Yasuhiro,Maeda, Kenji,Mitsuya, Hiroaki
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p. 1869 - 1873
(2007/10/03)
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- Discovery of imidazolidine-2,4-dione-linked HIV protease inhibitors with activity against lopinavir-resistant mutant HIV
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A new series of HIV protease inhibitors has been designed and synthesized based on the combination of the (R)-(hydroxyethylamino)sulfonamide isostere and the cyclic urea component of lopinavir. The series was optimized by replacing the 6-membered cyclic urea linker with an imidazolidine-2,4-dione which readily underwent N-alkylation to incorporate various methylene-linked heterocycle groups that bind favorably in site 3 of HIV protease. Significant improvements compared to lopinavir were seen in cell culture activity versus wild-type virus (pNL4-3) and the lopinavir-resistant mutant virus A17 (generated by in vitro serial passage of HIV-1 (pNL4-3) in MT-4 cells). Select imidazolidine-2,4-dione containing PIs were also more effective at inhibiting highly resistant patient isolates Pt1 and Pt2 than lopinavir. Pharmacokinetic data collected for compounds in this series varied considerably when coadministered orally in the rat with an equal amount of ritonavir (5 mg/kg each). The AUC values ranged from 0.144 to 12.33 μg h/mL.
- Flosi, William J.,DeGoey, David A.,Grampovnik, David J.,Chen, Hui-ju,Klein, Larry L.,Dekhtyar, Tatyana,Masse, Sherie,Marsh, Kennan C.,Mo, Hong Mei,Kempf, Dale
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p. 6695 - 6712
(2007/10/03)
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- Discovery of HIV-1 protease inhibitors with picomolar affinities incorporating N-aryl-oxazolidinone-5-carboxamides as novel P2 ligands
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Here, we describe the design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors incorporating N-phenyloxazolidinone-5-carboxamides into the (hydroxyethylamino)sulfonamide scaffold as P2 ligands. Series of inhibitors with variations at the P2 phenyloxazolidinone and the P2′ phenylsulfonamide moieties were synthesized. Compounds with the (S)-enantiomer of substituted phenyloxazolidinones at P2 show highly potent inhibitory activities against HIV-1 protease. The inhibitors possessing 3-acetyl, 4-acetyl, and 3-trifluoromethyl groups at the phenyl ring of the oxazolidinone fragment are the most potent in each series, with Ki values in the low picomolar (pM) range. The electron-donating groups 4-methoxy and 1,3-dioxolane are preferred at P2′ phenyl ring, as compounds with other substitutions show lower binding affinities. Attempts to replace the isobutyl group at P1′ with small cyclic moieties caused significant loss of affinities in the resulting compounds. Crystal structure analysis of the two most potent inhibitors in complex with the HIV-1 protease provided valuable information on the interactions between the inhibitor and the protease enzyme. In both inhibitor-enzyme complexes, the carbonyl group of the oxazolidinone ring makes hydrogen-bond interactions with relatively conserved Asp29 residue of the protease. Potent inhibitors from each series incorporating various phenyloxazolidinone based P2 ligands were selected and their activities against a panel of multidrug-resistant (MDR) protease variants were determined. Interestingly, the most potent protease inhibitor starts out with extremely tight affinity for the wild-type enzyme (Ki = 0.8 pM), and even against the MDR variants it retains picomolar to low nanomolar Ki, which is highly comparable with the best FDA-approved protease inhibitors.
- Ali, Akbar,Reddy, G. S. Kiran Kumar,Cao, Hong,Anjum, Saima Ghafoor,Nalam, Madhavi N. L.,Schiffer, Celia A.,Rana, Tariq M.
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p. 7342 - 7356
(2007/10/03)
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- HIV protease inhibiting compounds
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A compound of the formula is disclosed as an HIV protease inhibitor. Methods and compositions for inhibiting an HIV infection are also disclosed.
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Page/Page column 62
(2010/02/12)
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- Oximinoarylsulfonamides as potent HIV protease inhibitors
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The need for a potent HIV protease inhibitor (PI) to combat emerging PI-resistant viruses is anticipated. Analogs formulated from the combination of structural fragments of Ritonavir, Lopinavir, and Amprenavir were synthesized. Analogs containing the oxime pharmacophore were found to have improved activities against both wild type and resistant (A17) viruses. The synthesis and structure-activity relationships (SAR) based upon the in vitro IC50 of this series of compounds are reported.
- Yeung, Clinton M.,Klein, Larry L.,Flentge, Charles A.,Randolph, John T.,Zhao, Chen,Sun, MingHua,Dekhtyar, Tatyana,Stoll, Vincent S.,Kempf, Dale J.
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p. 2275 - 2278
(2007/10/03)
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- Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor
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The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2′ substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high enthalpy driven affinity of TMC114 for HIV-1 protease. In vitro selection of mutants resistant to TMC114 starting from wild-type virus proved to be extremely difficult; this was not the case for other close analogues. Therefore, the extra H-bond to the backbone in the P2 pocket cannot be the only explanation for the interesting antiviral profile of TMC114. Absorption studies in animals indicated that TMC114 has pharmacokinetic properties comparable to currently approved HIV-1 protease inhibitors.
- Surleraux, Dominique L. N. G.,Tahri, Abdellah,Verschueren, Wim G.,Pille, Geert M. E.,De Kock, Herman A.,Jonckers, Tim H. M.,Peeters, Anik,De Meyer, Sandra,Azijn, Hilde,Pauwels, Rudi,De Bethune, Marie-Pierre,King, Nancy M.,Prabu-Jeyabalan, Moses,Schiffer, Celia A.,Wigerinck, Piet B. T. P.
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p. 1813 - 1822
(2007/10/03)
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