- Identification of novel uracil derivatives incorporating benzoic acid moieties as highly potent Dipeptidyl Peptidase-IV inhibitors
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Dipeptidyl Peptidase-IV (DPP-4) is a validated therapeutic target for type 2 diabetes. Aiming to interact with both residues Try629 and Lys554 in S2′ site, a series of novel uracil derivatives 1a–l and 2a–i incorporating benzoic acid moieties at the N3 position were designed and evaluated for their DPP-4 inhibitory activity. Structure-activity relationships (SAR) study led to the identification of the optimal compound 2b as a potent and selective DPP-4 inhibitor (IC50 = 1.7 nM). Docking study revealed the additional salt bridge formed between the carboxylic acid and primary amine of Lys554 has a key role in the enhancement of the activity. Furthermore, compound 2b exhibited no cytotoxicity in human hepatocyte LO2 cells up to 50 μM. Subsequent in vivo evaluations revealed that the ester of 2b robustly improves the glucose tolerance in normal mice. The overall results have shown that compound 2b has the potential to a safe and efficacious treatment for T2DM.
- Huang, Junli,Deng, Xiaoyan,Zhou, Siru,Wang, Na,Qin, Yujun,Meng, Liuwei,Li, Guobao,Xiong, Yuhua,Fan, Yating,Guo, Ling,Lan, Danni,Xing, Junhao,Jiang, Weizhe,Li, Qing
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- Rapid generation of novel benzoic acid–based xanthine derivatives as highly potent, selective and long acting DPP-4 inhibitors: Scaffold-hopping and prodrug study
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A series of novel xanthine derivatives 2a-l incorporating benzoic acid moieties were rapidly generated by using strategy of scaffold-hopping from our previously reported scaffold uracil to xanthine, a scaffold of approved drug linagliptin. After systematic structure-activity relationship (SAR) study around benzoic acid moieties, 5 novel DPP-4 inhibitors with low picomolar potency range (IC50 50 value of 0.1 nM for DPP-4, showed 22-fold improvement in inhibitory activity compared to lead compound uracil 1, its activity was 45-fold more potent than alogliptin. 2e, 2f, 2i and 2k were selected for pharmacokinetic evaluation, and 2f and 2i showed the better pharmacokinetic profiles after iv administration, but poor oral bioavailability. To improve the oral pharmacokinetic profile, prodrug design approach was performed around 2f and 2i. Esters of 2f and 2i were synthesized and evaluated for stability, toxicity and pharmacokinetics. Compound 3e, the methyl ester of compound 2f, was identified to demonstrate good stability, low toxicity and improved oral bioavailability, with 3-fold higher blood concentration compared to 2f in rats. The following in vivo evaluations revealed 3e provided a sustained pharmacodynamics effect for 48h, and robustly improved glucose tolerance in normal ICR and db/db mice in dose-dependent manner. Chronic treatments investigations demonstrated that 3e achieved more beneficial effects on fasting blood glucose levels and glucose tolerance than alogliptin in type 2 diabetic db/db mice. The overall results have shown that compound 3e has the potential to efficacious, safety and long-acting treatment for T2DM.
- Li, Qing,Meng, Liuwei,Zhou, Siru,Deng, Xiaoyan,Wang, Na,Ji, Yi,Peng, Yichun,Xing, Junhao,Yao, Gongmei
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- Copper-promoted direct amidation of isoindolinone scaffolds by sodium persulfate
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Isoindolinones are ubiquitous structural motifs in natural products and pharmaceuticals. Establishing an efficient method for structural modification of isoindolinones could significantly facilitate new drug development. Herein, we describe copper-promoted direct amidation of isoindolinone scaffolds mediated by sodium persulfate. The method exhibits mild reaction conditions and high site-selectivity, and enables the structural modification of the drug indobufen ester with various amides with yields of 49 to 98%. It is also gram-scalable. Additionally, the reaction mechanism appears to involve a radical and a carbocationic pathway.
- Lai, Huifang,Lin, Jin,Xu, Jiexin,Zha, Daijun
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supporting information
p. 7621 - 7626
(2021/09/22)
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- Br?nsted Acid Catalyzed Dearomatization by Intramolecular Hydroalkoxylation/Claisen Rearrangement: Diastereo- and Enantioselective Synthesis of Spirolactams
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Described herein is a novel Br?nsted acid catalyzed intramolecular hydroalkoxylation/Claisen rearrangement, allowing the practical and atom-economic synthesis of a range of valuable spirolactams from readily available ynamides in generally good to excellent yields with excellent diastereoselectivities and broad substrate scope. Importantly, an unexpected dearomatization of nonactivated arenes and heteroaromatic compounds is involved in this tandem sequence. Moreover, an asymmetric version of this tandem cyclization was also achieved by efficient kinetic resolution by chiral phosphoric acid catalysis. In addition, the [3,3]-rearrangement is shown to be kinetically preferred over the related [1,3]-rearrangement by theoretical calculations.
- Chen, Peng-Fei,Wang, Binju,Wu, Peng,Ye, Long-Wu,Zhou, Bo
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supporting information
p. 27164 - 27170
(2021/11/22)
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- Uracil derivatives containing benzene carboxylic acid or benzamide and preparation method and medical application thereof
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The invention relates to uracil derivatives containing benzene carboxylic acid or benzamide, and a preparation method and medical application thereof. Specifically, the present invention relates to the novel uracil derivatives as shown in a general formul
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Paragraph 0018-0019; 0022
(2020/05/30)
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- Influenza virus replication inhibitor and uses thereof
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The invention belongs to the field of medicines, and particularly relates to a new compound serving as an influenza virus replication inhibitor, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound and the pharmaceutical composition in the treatment of influenza. The compound is a compound shown in a formula (I) or a stereoisomer, a tautomer, oxynitride, a solvate, a metabolite, a pharmaceutically acceptable salt or prodrugs of the compound shown in the formula (I). The compound can well inhibit influenza viruses, and/or has lowercytotoxicity, more excellent in-vivo metabolic dynamics properties and in-vivo pharmacodynamic properties.
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Paragraph 0530; 0532-0534
(2020/05/05)
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- INFLUENZA VIRUS REPLICATION INHIBITOR AND USES THEREOF
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The invention belongs to the field of medicine, and particularly relates to a novel compound as a replication inhibitor of influenza virus and a preparation method thereof, a pharmaceutical composition comprising the compound and use of the compound and pharmaceutical composition thereof in treating influenza. The present invention provides a compound having Formula (I) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, The compound of the present invention can inhibit influenza virus well, and/or has lower cytotoxicity, better in vivo pharmacokinetic properties and in vivo pharmacodynamic properties.
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Paragraph 00294-00295
(2020/05/21)
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- Copper-catalyzed C-N coupling in the synthesis of integrase inhibitors of immunodeficiency viruses
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This contribution describes the total synthesis of a complex macrocyclic integrase inhibitor, a key enzyme involved in the infection process of various immunodeficiency viruses. The key transformation of the synthetic strategy was the selective C-N coupling of a sulfonamide to a heteroaryl bromide in the presence of potentially competing amide and carbamate functionalities. The transformation was accomplished with CuI catalysis using bypiridine as the ligand in the presence of base and enabled a convergent approach to the target molecule.
- Lin, Jinguan,Houpis, Ioannis N.,Liu, Renmao,Wang, Youchu,Zhang, Jianqian
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p. 205 - 214
(2014/05/20)
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- Design, synthesis, and structure-activity relationship studies of conformationally restricted mutilin 14-carbamates
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We report herein the design, synthesis, and structure-activity relationship studies of conformationally restricted mutilin 14-carbamates based on the structure of SB-222734. The antibacterial activities of these newly synthesized compounds were also evaluated and compared with linezolid and retapamulin. Results showed that most of the target compounds exhibit good potency in inhibiting the growth of Gram-positive bacteria including Methicillin- susceptible Staphylococcus aureus MSSA (MIC: 0.0625-2 μg/mL), Methicillin-resistant S. aureus MRSA (MIC: 0.0625-2 μg/mL), Methicillin-susceptible Staphylococcus epidermidis MSSE (MIC: 0.0625-2 μg/mL), Methicillin-resistant S. epidermidis MRSE (MIC: 0.0625-2 μg/mL), and Streptococcus pneumonia (MIC: 0.0625-4 μg/mL). In particular, three remarkable compounds of this series (12l, 12m, and 21l) exhibited comparable in vitro antibacterial profiles to that of retapamulin.
- Fu, Liqiang,Liu, Xin,Ling, Chenyu,Cheng, Jianjun,Guo, Xingsheng,He, Huili,Ding, Shi,Yang, Yushe
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scheme or table
p. 814 - 819
(2012/03/11)
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- Biaryl substituted hydantoin compounds as TACE inhibitors
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We disclose further optimization of hydantoin TNF-α convertase enzyme (TACE) inhibitors. SAR with respect to the non-prime region of TACE active site was explored. A series of biaryl substituted hydantoin compounds was shown to have sub-nanomolar Ki
- Yu, Wensheng,Tong, Ling,Kim, Seong Heon,Wong, Michael K.C.,Chen, Lei,Yang, De-Yi,Shankar, Bandarpalle B.,Lavey, Brian J.,Zhou, Guowei,Kosinski, Aneta,Rizvi, Razia,Li, Dansu,Feltz, Robert J.,Piwinski, John J.,Rosner, Kristin E.,Shih, Neng-Yang,Siddiqui, M. Arshad,Guo, Zhuyan,Orth, Peter,Shah, Himanshu,Sun, Jing,Umland, Shelby,Lundell, Daniel J.,Niu, Xiaoda,Kozlowski, Joseph A.
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scheme or table
p. 5286 - 5289
(2010/10/18)
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- COMPOUNDS FOR TREATING VIRAL INFECTIONS
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The invention relates to compounds, pharmaceutical compositions and methods useful for treating viral infection.
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Page/Page column 82
(2008/12/08)
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- Isoindol-1,3-dione and isoindol-1-one derivatives with high binding affinity to β-amyloid fibrils
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Based on the structural features of Indoprofen and PIB, a series of isoindol-1,3-diones 1a-k and isoindol-1-ones 2a-l were designed and synthesized. These 23 compounds were evaluated by competitive binding assay against aggregated Aβ42 fibrils using [125I]TZDM. All the isoindolone derivatives showed very good binding affinities with Ki values in the subnanomolar range (0.42-0.94 nM). Among them, isoindol-1,3-diones 1i and 1k and isoindol-1-ones 2c and 2i exhibited excellent binding affinities (Ki = 0.42-0.44 and 0.46-0.49 nM) than those of Indoprofen (Ki = 0.52 nM) and PIB (Ki = 0.70 nM). These results suggest that isoindolones could be served as a scaffold for potential AD diagnostic probes to monitor Aβ fibrils.
- Lee, Hyu Ji,Lim, Soo Jeong,Oh, Seung Jun,Moon, Dae Hyuk,Kim, Dong Jin,Tae, Jinsung,Yoo, Kyung Ho
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p. 1628 - 1631
(2008/09/19)
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- A potent and orally active HIV-1 integrase inhibitor
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A 1,6-naphthyridine inhibitor of HIV-1 integrase has been discovered with excellent inhibitory activity in cells, good pharmacokinetics, and an excellent ability to inhibit virus with mutant enzyme.
- Egbertson, Melissa S.,Moritz, H. Marie,Melamed, Jeffrey Y.,Han, Wei,Perlow, Debra S.,Kuo, Michelle S.,Embrey, Mark,Vacca, Joseph P.,Zrada, Matthew M.,Cortes, Amanda R.,Wallace, Audrey,Leonard, Yvonne,Hazuda, Daria J.,Miller, Michael D.,Felock, Peter J.,Stillmock, Kara A.,Witmer, Marc V.,Schleif, William,Gabryelski, Lori J.,Moyer, Gregory,Ellis, Joan D.,Jin, Lixia,Xu, Wei,Braun, Matthew P.,Kassahun, Kellem,Tsou, Nancy N.,Young, Steven D.
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p. 1392 - 1398
(2007/10/03)
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- 4-CARBOXY PYRAZOLE DERIVATIVES AS ANTI-VIRAL AGENTS
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Anti-viral agents of compounds of Formula (I): wherein A, R1, R2, R3 and R4 are as defined in the specification, processes for their preparation and their use in HCV treatment are provided.
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Page/Page column 49
(2010/11/26)
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- COMPOUNDS HAVING ACTIVITY AT 5HT2C RECEPTOR AND USES THEREOF
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Compounds of formula (I) and pharmaceutically acceptable salts thereof are disclosed: wherein R1 is halogen, cyano, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkyloxy, C1-6alkoxy, C1 6alkylthio, hydroxy, amino, mono or di C1 6alkylamino, an N-linked 4 to 7 memb
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Page 14; 15; 17
(2010/02/09)
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- Optimization of the Quinoline and Substituted Benzyl Moieties of a Series of Phenyltetrazole Leukotriene D4 Receptor Antagonists
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This report describes the development of a series of highly potent quinoline-based leukotriene D4 (LTD4) receptor antagonists containing an N-benzyl-substituted phenyltetrazole moiety.They were designed to provide both the correct positioning of the acidic function and secondary lipophilic domain required for strong receptor binding.Members of this series possess high activity in blocking LTD4-induced contractions of isolated guinea pig ileum.Compound 32, LY287192 (2-phenyl>-2H-tetrazol-2-yl>methyl>-5-fluorobenzoic acid sodium salt), blocked contraction with a pKB value of 9.1+/-0.3.Qualitative structure-activity studies have demonstrated specific requirements for the best activity.In particular, ortho substitution of the benzyl group with an acidic function was crucial for maximum potency.In cases similar to 32, where the benzyl group possesses an ortho carboxylate, the N-2-substituted tetrazole isomer showed 100-fold greater activity relative to the corresponding N-1 isomer.This pattern was reversed when the acid was substituted at the para position.The quinoline unit may be replaced by other nitrogen-containing heterocycles.
- Sawyer, J. Scott,Baldwin, Ronald F.,Rinkema, Lynn E.,Roman, Carlos R.,Fleisch, Jerome H.
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p. 1200 - 1209
(2007/10/02)
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