- Synthesis and structure-activity relationship of 7-(3'-amino-4'-methoxypyrrolidin-1'-yl)-1-cyclopropyl-6,8-difluoro-1,4 -dihydro-4-oxoquinoline-3-carboxylic acids
-
A new series of quinolone derivatives 3a-l bearing 3-amino-4-methoxypyrrolidines of different configurations and chirality were synthesized and their antibacterial activities as well as some of their toxicological properties were examined. As predicted by our previous quantitative structure-activity relationships (QSAR) analysis of C-7 heterocyclic amine substituted quinolonecarboxylic acid antibacterial agents, these pyrrolidine derivatives showed higher in vitro and in vivo antibacterial activities against both gram-positive and gram-negative bacteria than the analogs bearing various 3-substituted azetidines. Furthermore, the amino and methoxy substituent groups on the pyrrolidine ring exhibited strong configurational and chiral effects on the in vitro and in vivo antibacterial activities of these compounds: (1) cis compounds showed higher antibacterial activities against most of the pathogens examined; (2) N-methylation of the 3-amino group on the pyrrolidine ring lowered in vitro but not in vivo antibacterial activities, particularly leading to superior in vivo anti-pseudomonal activity; (3) the (3'S,4'R)-derivative showed substantially higher activity that the (3'R,4'S)-one. These findings led to the selection of compound 3k for further evaluation as it possessed the highest in vivo antibacterial activity and no cytotoxicity.
- Okada,Sato,Tsuji,Tsushima,Nakai,Yoshida,Matsuura
-
-
Read Online
- Synthesis of (±)-trans-hexahydropyrrolo[3,4-d]oxazol-2-one and its derivatives by using N-(tert-butyloxycarbonyl)-3-pyrroline as precursor
-
Synthetic method for the preparation of (±)-trans- hexahydropyrrolo[3,4-d]oxazol-2-one and its derivatives has been developed. By one route, an efficient preparation of these fused heterobicyclic moieties could be achieved, which are prepared by using N-(tert-butyloxycarbonyl)-3-pyrroline as precursor. These fused heterobicyclic systems could be useful to develop a series of 2-oxazolidinone analogues.
- Rajesh, Tammana,Rao, Sambangi Polinaini Narayana,Suresh, Kopparthi,Madhusudhan, Gutta,Mukkanti, Kagga
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Read Online
- Methyloxime-substituted aminopyrrolidine: A new surrogate for 7-basic group of quinolone
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Novel fluoroquinolones containing oxime functionalized aminopyrrolidines have been synthesized. They were found to possess potent antibacterial activities both Gram-negative and Gram-positive organisms, including methicillin resistant Staphylococcus aureus (MRSA). Among these compounds, LB20277 (compound 12) showed the most favorable in vivo efficacy and pharmacokinetic profile in animals. Based on these promising results, LB20277 was selected as a candidate for further evaluation.
- Hong, Chang Yong,Kim, Young Kwan,Lee, Yong Hee,Kwak, Jin Hwan
-
-
Read Online
- HETEROARYLDIHYDROPYRIMIDINE DERIVATIVES AND METHODS OF TREATING HEPATITIS B INFECTIONS
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Provided herein are compounds useful for the treatment of HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in the subject.
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Page/Page column 105-106
(2021/06/26)
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- JAK inhibitor compound and application thereof
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The invention relates to a JAK inhibitor compound and application thereof. Specifically, the invention discloses a compound shown as a formula (G), or an isotope labeled compound, or an optical isomer, a geometrical isomer, a tautomer or an isomer mixture of the compound, or a pharmaceutically acceptable salt of the compound, or a prodrug of the compound, or a metabolite of the compound. The invention also relates to the medical application of the compound.
- -
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Paragraph 0508; 0515; 0528-0530
(2020/09/12)
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- Compound as well as preparation method and medical application thereof
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The invention provides a compound as well as a preparation method and medical application thereof, the compound has a structure as shown in a general formula (I), and can also be a tautomer, a mesomer, a raceme, an enantiomer, a diastereoisomer, or a mixture form thereof, or a pharmaceutically acceptable salt thereof. According to the compound with the structure as shown in the general formula (I)provided by the invention, a specific main chain structure and a corresponding substituent group are selected, so that the obtained compound can be used as an arginase inhibitor, is relatively high in activity, and has a potential treatment prospect in various diseases.
- -
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Paragraph 0038; 0056-0059
(2020/02/14)
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- Synthesis of new (±)-1-(4-(3-fluorobenzyloxy)pyrrolidin-3-yl)-4-phenyl-1H-1,2,3-triazole derivatives via click reaction and study of anti-cancer activity against HCT 116, MDA-MB231, Mia-PaCa2 cell lines
-
ASERIES of 16 new (±) -1-(4-(3-fluorobenzyloxy) pyrrolidin-3-yl)-4-phenyl-1H-1,2,3-triazole derivatives were synthesized from 2,5-dihydro-1H-pyrrole. Sixteen compounds are well characterized by their 1H NMR, 13C NMR and mass spectral data. Anticancer activities of these compounds were tested against HCT 116, MDA-MB231, Mia-PaCa2 cancer cell lines. Among these series of compounds, 8b exhibited highest activity with IC50 of 42.5 μg/ mL against MDA-MB231 cell line. The compound 8o and 8n showed moderate activity with IC50 of 64.3 μg/ mL and 68.4 μg/ mL against HCT -116 and Mia-PaCa2 cancer cell lines respectively.
- Kumar, Gollapudi Ravi,Murthy Boddapati,Meruga, Santha Kumari,Bollikolla, Hari Babu
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p. 2813 - 2825
(2020/10/06)
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- SUBSTITUTED PYRROLIDINE COMPOUND AND USE THEREOF
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The present invention provides a substituted pyrrolidine compound having an orexin type 2 receptor agonist activity. A compound represented by the formula (I): wherein each symbol is as described in the specification, or a salt thereof, has an orexin type 2 receptor agonist activity, and is useful as an agent for the prophylaxis or treatment of narcolepsy.
- -
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Paragraph 0675-0676
(2020/12/25)
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- SUBSTITUTED PYRROLIDINE COMPOUND AND USE THEREOF
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The present invention provides a substituted pyrrolidine compound having an orexin type 2 receptor agonist activity. A compound represented by the formula (I): wherein each symbol is as described in the specification, or a salt thereof, has an orexin type 2 receptor agonist activity, and is useful as an agent for the prophylaxis or treatment of narcolepsy.
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Paragraph 0733; 0770; 0771
(2020/12/20)
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- Synthesis method of (3R,4S)-1-substituted-4-ethylpyrrole-3-carboxylic acid
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The invention discloses a synthesis method of (3R,4S)-1-substituted-4-ethylpyrrole-3-carboxylic acid, which comprises the following steps: reacting N-R-3-pyrroline with NBS (N-bromosuccinimide) to prepare an intermediate compound 2; adding the compound 2 into ethyl magnesium chloride or ethyl magnesium bromide for reaction to obtain an intermediate product compound 3; carrying out an oxidation reaction on the intermediate compound 3 to prepare an N-position protected intermediate product compound 4; reacting the intermediate compound 4 with a trifluoromethanesulfonylation reagent to prepare anintermediate product compound 5; introducing carbon monoxide gas into the intermediate compound 5, and reacting to obtain an intermediate compound 6; hydrolyzing the intermediate compound 6 to synthesize an intermediate compound 7; and carrying out an asymmetric reduction reaction on the intermediate compound 7 to prepare a high-chiral-purity product that is the (3R,4S)-1-substituted-4-ethylpyrrole-3-carboxylic acid. According to the synthesis method, the target product is prepared by adopting low-cost reaction raw materials, and the economic cost of the product process is reduced.
- -
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Paragraph 0047-0052; 0079-0084; 0111-0116
(2020/01/08)
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- FGFR4 INHIBITOR AND PREPARATION METHOD AND USE THEREOF
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Provided are a class of compounds as shown in formula (I) as FGFR4 inhibitors, and pharmaceutically acceptable salts thereof, preparation methods therefor and the use thereof in the preparation of drugs for treating FGFR4-related diseases.
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Paragraph 0409-0411
(2019/10/10)
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- THIOPHENE DERIVATIVES FOR THE TREATMENT OF DISORDERS CAUSED BY IGE
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Thiophene derivatives of formula (I) and a pharmaceutically acceptable salt thereof are provided. These compounds have utility for the treatment or prevention of disorders caused by IgE, such as allergy, type 1 hypersensitivity or familiar sinus inflammation.
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Page/Page column 263; 264
(2020/01/11)
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- NOVEL HETEROCYCLIC COMPOUNDS AS IRAK4 INHIBITORS
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The present invention relates to novel compounds of the general formula (I) their tautomeric forms, their enantiomers, their diastereoisomers, their pharmaceutically accepted salts, or pro-drugs thereof, which are useful for the treatment or prevention of cancer and inflammatory diseases associated with Interleukin-1 Receptor Associated Kinase (IRAK), and more particularly compounds that modulate the function of IRAK4.
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Page/Page column 32
(2019/06/23)
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- Design and Optimization of Sulfone Pyrrolidine Sulfonamide Antagonists of Transient Receptor Potential Vanilloid-4 with in Vivo Activity in a Pulmonary Edema Model
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Pulmonary edema is a common ailment of heart failure patients and has remained an unmet medical need due to dose-limiting side effects associated with current treatments. Preclinical studies in rodents have suggested that inhibition of transient receptor potential vanilloid-4 (TRPV4) cation channels may offer an alternative - and potentially superior - therapy. Efforts directed toward small-molecule antagonists of the TRPV4 receptor have led to the discovery of a novel sulfone pyrrolidine sulfonamide chemotype exemplified by lead compound 6. Design elements toward the optimization of TRPV4 activity, selectivity, and pharmacokinetic properties are described. Activity of leading exemplars 19 and 27 in an in vivo model suggestive of therapeutic potential is highlighted herein.
- Pero, Joseph E.,Matthews, Jay M.,Behm, David J.,Brnardic, Edward J.,Brooks, Carl,Budzik, Brian W.,Costell, Melissa H.,Donatelli, Carla A.,Eisennagel, Stephen H.,Erhard, Karl,Fischer, Michael C.,Holt, Dennis A.,Jolivette, Larry J.,Li, Huijie,Li, Peng,McAtee, John J.,McCleland, Brent W.,Pendrak, Israil,Posobiec, Lorraine M.,Rivera, Katrina L.K.,Rivero, Ralph A.,Roethke, Theresa J.,Sender, Matthew R.,Shu, Arthur,Terrell, Lamont R.,Vaidya, Kalindi,Xu, Xiaoping,Lawhorn, Brian G.
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supporting information
p. 11209 - 11220
(2019/01/04)
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- Tetrahydroisoquinoline compound and its preparation method, pharmaceutical composition and use
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The invention relates to a tetrahydroisoquinoline compound and its preparation method, pharmaceutical composition and use. The tetrahydroisoquinoline compound is shown by the general formula (1). In the general formula (1), the symbols have the same definitions as in the specification.
- -
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Paragraph 0210
(2018/03/24)
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- Discovery of Pyrrolidine Sulfonamides as Selective and Orally Bioavailable Antagonists of Transient Receptor Potential Vanilloid-4 (TRPV4)
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A novel series of pyrrolidine sulfonamide transient receptor potential vanilloid-4 (TRPV4) antagonists was developed by modification of a previously reported TRPV4 inhibitor (1). Several core-structure modifications were identified that improved TRPV4 activity by increasing structural rigidity and reducing the entropic energy penalty upon binding to the target protein. The new template was initially discovered as a minor regio-isomeric side product formed during routine structure-activity relationship (SAR) studies, and further optimization resulted in highly potent compounds with a novel pyrrolidine diol core. Further improvements in potency and pharmacokinetic properties were achieved through SAR studies on the sulfonamide substituent to give an optimized lead compound GSK3395879 (52) that demonstrated the ability to inhibit TRPV4-mediated pulmonary edema in an in vivo rat model. GSK3395879 is a tool for studying the biology of TRPV4 and an advanced lead for identifying new heart failure medicines.
- Brnardic, Edward J.,Ye, Guosen,Brooks, Carl,Donatelli, Carla,Barton, Linda,McAtee, Jeff,Sanchez, Robert M.,Shu, Arthur,Erhard, Karl,Terrell, Lamont,Graczyk-Millbrandt, Grazyna,He, Yanan,Costell, Melissa H.,Behm, David J.,Roethke, Theresa,Stoy, Patrick,Holt, Dennis A.,Lawhorn, Brian G.
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p. 9738 - 9755
(2018/10/31)
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- Discovery of N-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants
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Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechani
- Planken, Simon,Behenna, Douglas C.,Nair, Sajiv K.,Johnson, Theodore O.,Nagata, Asako,Almaden, Chau,Bailey, Simon,Ballard, T. Eric,Bernier, Louise,Cheng, Hengmiao,Cho-Schultz, Sujin,Dalvie, Deepak,Deal, Judith G.,Dinh, Dac M.,Edwards, Martin P.,Ferre, Rose Ann,Gajiwala, Ketan S.,Hemkens, Michelle,Kania, Robert S.,Kath, John C.,Matthews, Jean,Murray, Brion W.,Niessen, Sherry,Orr, Suvi T. M.,Pairish, Mason,Sach, Neal W.,Shen, Hong,Shi, Manli,Solowiej, James,Tran, Khanh,Tseng, Elaine,Vicini, Paolo,Wang, Yuli,Weinrich, Scott L.,Zhou, Ru,Zientek, Michael,Liu, Longqing,Luo, Yiqin,Xin, Shuibo,Zhang, Chengyi,Lafontaine, Jennifer
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supporting information
p. 3002 - 3019
(2017/04/24)
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- Pyrrole imidazole ring derivative and medical use thereof wherein the compound represented by the general formula (I) has excellent inhibitory effect on and selectivity of dipeptidyl peptidase IV(DPP-IV)
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The present invention relates to a pyrrole imidazole ring derivative and medical use thereof, more particularly a pyrrole imidazole ring derivative represented by the general formula (I) or stereoisomers thereof, pharmaceutically acceptable salts thereof, prodrugs, pharmaceutical compositions containing the derivative, and pharmaceutical applications for the preparation of dipeptidyl peptidase IV(DPP-IV) inhibitors, wherein the definitions of all substitution groups in general formula (I) are the same as those defined in the specification.
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Page/Page column 61; 62
(2017/08/02)
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- FUSED QUADRACYCLIC COMPOUNDS, COMPOSITIONS AND USES THEREOF
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Provided herein are substituted fused quadracyclic compounds useful as inhibitors of MK2. The invention further provides pharmaceutical compositions of the compounds of the invention. The invention also provides medical uses of substituted fused quadracyclic compounds.
- -
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Paragraph 0378
(2017/08/01)
-
- Core chemotype diversification in the HIV-1 entry inhibitor class using field-based bioisosteric replacement
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Demand remains for new inhibitors of HIV-1 replication and the inhibition of HIV-1 entry is an extremely attractive therapeutic approach. Using field-based bioisosteric replacements, we have further extended the chemotypes available for development in the HIV-1 entry inhibitor class. Moreover, using field-based disparity analysis of the compounds, 3D structure-activity relationships were derived that will be useful in the further development of these inhibitors towards clinical utility.
- Tuyishime, Marina,Lawrence, Rae,Cocklin, Simon
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supporting information
p. 228 - 234
(2015/12/20)
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- PURINE DERIVATIVES
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The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein Q, G, ring A, ring B, R1, R2, R3, R4, R5, R5a, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, and m are defined herein. The novel purine derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. Additional embodiments relate to pharmaceutical compositions containing the compounds and to methods of using the compounds and compositions in the treatment of abnormal cell growth in mammals.
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Paragraph 0683; 0684
(2015/05/26)
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- Synthesis, antimycobacterial and antibacterial activity of l-[(1R,2S)-2-fluorocyclopropyl]naphthyridone derivatives containing an oxime-functionalized pyrrolidine moiety
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A series of novel 1-[(1R,2S)-2-fluorocyclopropyl]naphthyridone derivatives 21-24 containing an oxime-functionalized pyrrolidine moiety were designed, synthesized and evaluated for their biological activity. Our results reveal that compounds 21a, 21e and 21j show considerable activity against MTB H37Rv ATCC 27294 (MICs: 250 times more potent than ciprofloxacin and levofloxacin.
- Huang, Ju,Liu, Hongtao,Liu, Mingliang,Zhang, Rui,Li, Linhu,Wang, Bin,Wang, Minghua,Wang, Chunlan,Lu, Yu
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p. 5058 - 5063
(2015/11/09)
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- Highly enantioselective organocatalytic oxidative kinetic resolution of secondary alcohols using chiral alkoxyamines as precatalysts: Catalyst structure, active species, and substrate scope
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The development and characterization of enantioselective organocatalytic oxidative kinetic resolution (OKR) of racemic secondary alcohols using chiral alkoxyamines as precatalysts are described. A number of chiral alkoxyamines have been synthesized, and their structure-enantioselectivity correlation study in OKR has led us to identify a promising precatalyst, namely, 7-benzyl-3-n-butyl-4-oxa-5-azahomoadamantane, which affords various chiral aliphatic secondary alcohols (ee up to >99%, krel up to 296). In a mechanistic study, chlorine-containing oxoammonium species were identified as the active species generated in situ from the alkoxyamine precatalyst, and it was revealed that the chlorine atom is crucial for high reactivity and enantioselectivity. The present OKR is the first successful example applicable to various unactivated aliphatic secondary alcohols, including heterocyclic alcohols with high enantioselectivity, the synthetic application of which is demonstrated by the synthesis of a bioactive compound.
- Murakami, Keiichi,Sasano, Yusuke,Tomizawa, Masaki,Shibuya, Masatoshi,Kwon, Eunsang,Iwabuchi, Yoshiharu
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supporting information
p. 17591 - 17600
(2015/02/19)
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- Enzyme-catalyzed kinetic resolution of N-Boc-trans-3-hydroxy-4- phenylpyrrolidine
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The first enzyme-catalyzed kinetic resolution of tert-butyl-3-hydroxy-4- phenylpyrrolidine-1-carboxylate is presented. Enzyme, solvent and temperature optimization resulted in a new resolution method with E = 40 enantioselectivity. The acetate derivative of the (+)-(3S,4R) enantiomer formed while the (-)-(3R,4S) isomer remained intact. Very good enantioselectivities (E > 200) were achieved in the enzyme-catalyzed alcoholysis of the racemic acetate in i-propanol and t-butanol where the (+)-(3S,4R) enantiomer was prepared in pure form (ee > 99.7%). Absolute configuration of the (-)-(3R,4S)-enantiomer was determined by single crystal X-ray diffraction method. [Figure not available: see fulltext.]
- Faigl, Ferenc,Kovacs, Ervin,Balogh, Dora,Holczbauer, Tamas,Czugler, Matyas,Simandi, Bela
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- NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS
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The present invention discloses compounds according to Formula I: Wherein R 1a, R 1b, R 2, R 4, R5, R 6, R 7, R 8, W, X, Y, Z, Cy, and the subscript a are as defined h
- -
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Paragraph 00491; 00492
(2015/01/07)
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- A broadly applicable and practical oligomeric (salen)Co catalyst for enantioselective epoxide ring-opening reactions
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The (salen)Co catalyst (4a) can be prepared as a mixture of cyclic oligomers in a short, chromatography-free synthesis from inexpensive, commercially available precursors. This catalyst displays remarkable enhancements in reactivity and enantioselectivity relative to monomeric and other multimeric (salen)Co catalysts in a wide variety of enantioselective epoxide ring-opening reactions. The application of catalyst 4a is illustrated in the kinetic resolution of terminal epoxides by nucleophilic ring-opening with water, phenols, and primary alcohols; the desymmetrization of meso epoxides by addition of water and carbamates; and the desymmetrization of oxetanes by intramolecular ring opening with alcohols and phenols. The favorable solubility properties of complex 4a under the catalytic conditions facilitated mechanistic studies, allowing elucidation of the basis for the beneficial effect of oligomerization. Finally, a catalyst selection guide is provided to delineate the specific advantages of oligomeric catalyst 4a relative to (salen)Co monomer 1 for each reaction class.
- White, David E.,Tadross, Pamela M.,Lu, Zhe,Jacobsen, Eric N.
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supporting information
p. 4165 - 4180
(2014/06/09)
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- HEPATITIS B ANTIVIRAL AGENTS
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The present invention includes a method of inhibiting, suppressing or preventing HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of at least one compound of the invention.
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Page/Page column 221
(2013/07/05)
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- Matrix metalloproteinase inhibitors based on the 3-mercaptopyrrolidine core
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New series of pyrrolidine mercaptosulfide, 2-mercaptocyclopentane arylsulfonamide, and 3-mercapto-4-arylsulfonamidopyrrolidine matrix metalloproteinase inhibitors (MMPIs) were designed, synthesized, and evaluated. Exhibiting unique properties over other MMPIs (e.g., hydroxamates), these newly reported compounds are capable of modulating activities of several MMPs in the low nanomolar range, including MMP-2 (～2 to 50 nM), MMP-13 (～2 to 50 nM), and MMP-14 (～4 to 60 nM). Additionally these compounds are selective to intermediate- and deep-pocket MMPs but not shallow-pocketed MMPs (e.g., MMP-1, ～850 to >50 000 nM; MMP-7, ～4000 to >25 000 nM). Our previous work with the mercaptosulfide functionality attached to both cyclopentane and pyrrolidine frameworks demonstrated that the cis-(3S,4R)-stereochemistry was optimal for all of the MMPs tested. However, in our newest compounds an interesting shift of preference to the trans form of the mercaptosulfonamides was observed with increased oxidative stability and biological compatibility. We also report several kinetic and biological characteristics showing that these compounds may be used to probe the mechanistic activities of MMPs in disease.
- Jin, Yonghao,Roycik, Mark D.,Bosco, Dale B.,Cao, Qiang,Constantino, Manuel H.,Schwartz, Martin A.,Sang, Qing-Xiang Amy
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p. 4357 - 4373
(2013/07/19)
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- COMPOUNDS AND METHODS FOR ANTIVIRAL TREATMENT
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Compounds and pharmaceutically acceptable salts and esters and compositions thereof, for treating viral infections are provided. The compounds and compositions are useful for treating Pneumovirinae virus infections. The compounds, compositions, and methods provided are particularly useful for the treatment of Human respiratory syncytial virus infections
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- SUBSTITUTED CYCLIC COMPOUNDS AND METHODS OF USE
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The present invention provides novel substituted cyclic compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating cellular activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
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- SPECIFIC NNOS INHIBITORS FOR THE THERAPY AND PREVENTION OF HUMAN MELANOMA
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Methods for melanoma treatment and prevention with selective nitric oxide synthase inhibitor compounds and related pharmaceutical compositions, alone or in conjunction with one or more other melanoma therapies.
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Page/Page column 12-13
(2012/07/28)
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- Substituted Heterocyclic Mercaptosulfonamide Metalloprotease Inhibitors
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The present invention generally relates to substituted heterocyclic mercaptosulfonamide compounds, precursors, and derivatives as well as methods for the preparation of and pharmaceutical compositions comprising these compounds. These compounds are designed to be potent selective inhibitors of matrix metalloproteinases (MMPs), including, for example, gelatinases, collagenases, matrilysins, metalloelastase, stromelysin, and membrane-type 1 matrix metalloproteinase. These inhibitors may be used for the control of physiological and pathological processes and disease conditions in which MMPs are believed to play significant functions.
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Page/Page column 25
(2011/06/26)
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- 3-HYDROXYPYRROLIDINE INHIBITORS OF 5?-METHYLTHIOADENOSINE PHOSPHORYLASE AND NUCLEOSIDASE
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The present invention relates to 3-hydroxypyrrolidine compounds of the general formula (I) which are inhibitors of 5?-methylthioadenosine phosphorylase or 5?-methylthioadenosine nucleosidase. The invention also relates to the use of these compounds in the treatment of diseases or conditions in which it is desirable to inhibit 5?-methylthioadenosine phosphorylase or 5?-methylthioadenosine nucleosidase including cancer, and to pharmaceutical compositions containing the compounds
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Page/Page column 42
(2011/02/24)
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- FUSED HETEROCYCLIC COMPOUND
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The present invention relates to a fused heterocyclic compound having the Formula 1, which is useful as a platelet aggregation inhibitor, a method for preparing the same, and a pharmaceutical composition for inhibiting platelet aggregation comprising the same.
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Page/Page column 67
(2011/07/29)
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- STABLE SNS-595 COMPOSITIONS AND METHODS OF PREPARATION
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Methods of preparing substantially pure SNS-595 substance are disclosed. Also provided are compositions comprising SNS-595 substance that are substantially pure and essentially free of visible particles.
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- CARBAPENEM ANTIBACTERIALS WITH GRAM-NEGATIVE ACTIVITY
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The present invention provides β-methyl carbapenem compounds and pharmaceutical compositions useful in the treatment of bacterial infections and methods for treating such infections using such compounds and/or compositions. The invention includes administering an effective amount of a carbapenem compound or salt and/or prodrug thereof to a host in need of such a treatment.
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Page/Page column 116-117
(2012/01/06)
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- Design and synthesis of potent "sulfur-free" transition state analogue inhibitors of 5′-methylthioadenosine nucleosidase and 5′-methylthioadenosine phosphorylase
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5′-Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is a dual substrate bacterial enzyme involved in S-adenosylmethionine (SAM) related quorum sensing pathways that regulates virulence in many bacterial species. MTANs from many bacteria are directly involved in the quorum sensing mechanism by regulating the synthesis of autoinducer molecules that are used by bacterial communities to communicate. In humans, 5′-methylthioadenosine phosphorylase (MTAP) is involved in polyamine biosynthesis as well as in purine and SAM salvage pathways and thus has been identified as an anticancer target. Previously we have described the synthesis and biological activity of several aza-C-nucleoside mimics with a sulfur atom at the 5′ position that are potent E. coli MTAN and human MTAP inhibitors. Because of the possibility that the sulfur may affect bioavailability, we were interested in synthesizing "sulfur-free" analogues. Herein we describe the preparation of a series of "sulfur-free" transition state analogue inhibitors of E. coli MTAN and human MTAP that have low nano-to picomolar dissociation constants and are potentially novel bacterial anti-infective and anticancer drug candidates.
- Longshaw, Alistair I.,Adanitsch, Florian,Gutierrez, Jemy A.,Evans, Gary B.,Tyler, Peter C.,Schramm, Vern L.
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experimental part
p. 6730 - 6746
(2010/12/24)
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- COMPOUNDS FOR TREATING DISORDERS MEDIATED BY METABOTROPIC GLUTAMATE RECEPTOR 5, AND METHODS OF USE THEREOF
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Provided herein are compounds and methods of synthesis thereof. The compounds provided herein are useful for the treatment, prevention, and/or management of various disorders, such as neurological disorders, psychiatric disorders, neuromuscular disorders, gastrointestinal disorders, lower urinary tract disorder, and cancer. Compounds provided herein modulate the activity of metabotropic glutamate receptor 5 (mGluR5) in the central nervous system or the periphery. Pharmaceutical formulations containing the compounds and their methods of use are also provided herein.
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Page/Page column 153
(2010/11/03)
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- COMPOUNDS AND COMPOSITIONS FOR TREATMENT OF CANCER
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Compounds and compositions for treating, preventing or managing cancer are disclosed. The compositions provided herein comprise SNS-595 and N-desmethyl-SNS-595. Also provided are pharmaceutical compositions comprising the compounds and methods of treatment using the compounds and compositions.
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Page/Page column 16
(2010/03/02)
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- Exploration of the active site of neuronal nitric oxide synthase by the design and synthesis of pyrrolidinomethyl 2-aminopyridine derivatives
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Neuronal nitric oxide synthase (nNOS) represents an important therapeutic target for the prevention of brain injury and the treatment of various neurodegenerative disorders. A series of trans-substituted amino pyrrolidinomethyl 2-aminopyridine derivatives
- Ji, Haitao,Delker, Silvia L.,Li, Huiying,Martásek, Pavel,Roman, Linda J.,Poulos, Thomas L.,Silverman, Richard B.
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scheme or table
p. 7804 - 7824
(2011/02/25)
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- METHOD OF PREPARING (+)-1,4-DIHYDRO-7-[(3S,4S)-3METHOXY-4-(METHYLAMINO)-1-PYRROLIDINYL]-4-OXO-1-(2-THIAZOLYL)-1,8-NAPHTHYRIDINE-3-CARBOXYLIC ACID
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Methods of preparing (+)-1, 4-dihydro-7-[(3S,45)-3-methoxy-4-(methylamino)-1 - pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid are disclosed. Also provided are pharmaceutical compositions comprising (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, and methods of treatment using such compositions.
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Page/Page column 36
(2010/08/04)
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- Synthesis and enzymatic evaluation of 2- and 4-aminothiazole-based inhibitors of neuronal nitric oxide synthase
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Highly potent and selective inhibitors of neuronal nitric oxide synthase (nNOS) possessing a 2-aminopyridine group were recently designed and synthesized in our laboratory and were shown to have significant in vivo efficacy. In this work, analogs of our lead compound possessing 2- and 4-aminothiazole rings in place of the aminopyridine were synthesized. The less basic aminothiazole rings will be less protonated at physiological pH than the aminopyridine ring, and so the molecule will carry a lower net charge. This could lead to an increased ability to cross the blood-brain barrier thereby increasing the in vivo potency of these compounds. The 2-aminothiazole-based compound was less potent than the 2-aminopyridine-based analogue. 4-Aminothiazoles were unstable in water, undergoing tautomerization and hydrolysis to give inactive thiazolones.
- Lawton, Graham R.,Ji, Haitao,Silverman, Richard B.,Martasek, Pavel,Roman, Linda J.
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supporting information; experimental part
(2010/04/26)
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- Intramolecular azide-alkyne [3 + 2] cycloaddition: Versatile route to new heterocyclic structural scaffolds
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Investigating the relatively unexplored intramolecular version of the azide-alkyne [3 + 2] cycloaddition, the present studies demonstrate the utility of the above reaction in the synthesis of a variety of as yet unreported heterocyclic structural scaffolds. The approach involved initial installation of strategic azide and alkyne moieties on a common structural framework, followed by their intramolecular cycloaddition studies. The pivotal azidoalkyne intermediates were efficiently accessed from a variety of easily available starting materials such as olefins, epoxides, amino acids, amino alcohols, ketones etc. The key reactions for incorporation of the azide functionality into the desired framework involved azidolysis of epoxides, displacement of hydroxy groups with azide nucleophiles, and diazo transfer on amine. Attachment of the desired alkyne functionalities was accomplished by either N-, or, O-alkylation with appropriate propargylic halides. The azidoalkynes thus prepared underwent smooth intramolecular cycloaddition, resulting in a variety of novel triazolooxazine and triazolopyrazine derivatives. Interestingly, unlike in the intermolecular version, metal catalysis was not necessary for the performance of the above cycloadditions. It is expected that the results from the present studies and its further extension will provide a potentially fertile pathway to a variety of unique chemical entities of structural and biological significance.
- Li, Rongti,Jansen, Daniel J.,Datta, Apurba
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experimental part
p. 1921 - 1930
(2009/06/28)
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- THIENO-PYRIDINE DERIVATIVES AS MEK INHIBITORS
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A series of thieno[2,3-6]pyridine derivatives, attached at the 2-position to a substituted anilino moiety, which are substituted in the 3-position by a carbonyl group linked to a pyrrolidin-1-yl ring which in turn forms part of a heteroatom-containing fus
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Page/Page column 38
(2010/01/12)
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- Discovery of highly potent and selective inhibitors of neuronal nitric oxide synthase by fragment hopping
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Selective inhibition of neuronal nitric oxide synthase (nNOS) has been shown to prevent brain injury and is important for the treatment of various neurodegenerative disorders. This study shows that not only greater inhibitory potency and isozyme selectivity but more druglike properties can be achieved by fragment hopping. On the basis of the structure of lead molecule 6, fragment hopping effectively extracted the minimal pharmacophoric elements in the active site of nNOS for ligand hydrophobic and steric interactions and generated appropriate lipophilic fragments for lead optimization. More potent and selective inhibitors with better druglike properties were obtained within the design of 20 derivatives (compounds 7-26). Our structure - based inhibitor design for nNOS and SAR analysis reveal the robustness and efficiency of fragment hopping in lead discovery and structural optimization, which implicates a broad application of this approach to many other therapeutic targets for which known druglike small-molecule modulators are still limited.
- Ji, Haitao,Li, Huiying,Martásek, Pavel,Roman, Linda J.,Poulos, Thomas L.,Silverman, Richard B.
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scheme or table
p. 779 - 797
(2009/12/07)
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- Minimal pharmacophoric elements and fragment hopping, an approach directed at molecular diversity and isozyme selectivity. Design of selective neuronal nitric oxide synthase inhibitors
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Fragment hopping, a new fragment-based approach for de novo inhibitor design focusing on ligand diversity and isozyme selectivity, is described. The core of this approach is the derivation of the minimal pharmacophoric element for each pharmacophore. Sites for both ligand binding and isozyme selectivity are considered in deriving the minimal pharmacophoric elements. Five general-purpose libraries are established: the basic fragment library, the bioisostere library, the rules for metabolic stability, the toxicophore library, and the side chain library. These libraries are employed to generate focused fragment libraries to match the minimal pharmacophoric elements for each pharmacophore and then to link the fragment to the desired molecule. This method was successfully applied to neuronal nitric oxide synthase (nNOS), which is implicated in stroke and neurodegenerative diseases. Starting with the nitroarginine-containing dipeptide inhibitors we developed previously, a small organic molecule with a totally different chemical structure was designed, which showed nanomolar nNOS inhibitory potency and more than 1000-fold nNOS selectivity. The crystallographic analysis confirms that the small organic molecule with a constrained conformation can exactly mimic the mode of action of the dipeptide nNOS inhibitors. Therefore, a new peptidomimetic strategy, referred to as fragment hopping, which creates small organic molecules that mimic the biological function of peptides by a pharmacophore-driven strategy for fragment-based de novo design, has been established as a new type of fragment-based inhibitor design. As an open system, the newly established approach efficiently incorporates the concept of early "ADME/Tox" considerations and provides a basic platform for medicinal chemistry-driven efforts.
- Ji, Haitao,Stanton, Benjamin Z.,Igarashi, Jotaro,Li, Huiying,Martasek, Pavel,Roman, Linda J.,Poulos, Thomas L.,Silverman, Richard B.
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p. 3900 - 3914
(2008/12/20)
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- POTENT AND HIGHLY SELECTIVE HETEROAROMATIC INHIBITORS OF NEURONAL NITRIC OXIDE SYNTHASE
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Peptidomimetic compounds as can inhibit neuronal nitric oxide synthase (nNOS) for potential treatment in neurodegenerative diseases, such as but not limited to stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease.
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Page/Page column 18; 19-20; 33; 35-36
(2008/06/13)
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- NOS INHIBITORS FOR TREATMENT OF MOTOR DEFICIT DISORDERS
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The present invention relates to preventive therapies and treatments of motor deficit disorders. In particular, the present invention relates to compositions and methods for preventative therapy and treatment of motor deficit disorders, such as cerebral p
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Page/Page column 4; 5/8
(2008/06/13)
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- The discovery of potent, selective, and orally bioavailable hNK1 antagonists derived from pyrrolidine
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SAR studies on amides, ureas, and vinylogous amides derived from pyrrolidine led to the discovery of several potent hNK1 antagonists. One particular vinylogous amide (45b) had excellent potency, selectivity, pharmacokinetic profile, and functio
- Lin, Peter,Chang, Lehua,DeVita, Robert J.,Young, Jonathan R.,Eid, Ronsar,Tong, Xinchun,Zheng, Song,Ball, Richard G.,Tsou, Nancy N.,Chicchi, Gary G.,Kurtz, Marc M.,Tsao, Kwei-Lan C.,Wheeldon, Alan,Carlson, Emma J.,Eng, WaiSi,Burns, H. Donald,Hargreaves, Richard J.,Mills, Sander G.
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p. 5191 - 5198
(2008/03/13)
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- Substituted imidazole compounds as KSP inhibitors
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The present invention relates to new substituted imidazole compounds and pharmaceutically acceptable salts, esters or prodrugs thereof, compositions of the derivatives together with pharmaceutically acceptable carriers, and uses of the compounds. The compounds of the invention have the following general formula:
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Page/Page column 23
(2008/06/13)
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- Substituted 3-Amino-4-hydroxy pyrrolidines compounds, their preparation and use as medicaments
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The present invention relates to substituted pyrrolidine compounds of general formula (I), methods for their preparation, medicaments comprising these compounds as well as their use for the preparation of a medicament for the treatment of humans and animal.
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Page/Page column 90-91
(2008/06/13)
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- AMINOCYCLOHEXANES AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES
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The present invention is directed to novel substituted aminocyclohexanes of structural formula (I) which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.
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Page/Page column 39
(2008/06/13)
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