- Design and optimization of 2,3-dihydrobenzo[b][1,4]dioxine propanoic acids as novel GPR40 agonists with improved pharmacokinetic and safety profiles
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GPR40 has become a new potential therapeutic target for the treatment of diabetes due to its role in mediating the enhancement of glucose-stimulated insulin secretion in pancreatic β cells with a low risk of hypoglycemia. As an effort to extend the chemical space and identify structurally distinct GPR40 agonists with improved liver safety, a novel series of fused-ring phenyl propanoic acid analogues were designed. Comprehensive structure-activity relationship studies around novel scaffolds were conducted and led to several analogues exhibited potent GPR40 agonistic activities and high selectivity against other fatty acid receptors. Further evaluation of pharmacokinetic (PK) profiles and in vivo efficacy identified compound 40a with excellent PK properties and significant glucose-lowering efficacy during an oral glucose tolerance test. In addition, compound 40a displayed lower hepatobiliary transporter inhibition and favorable druggability. All results indicate that compound 40a is a promising candidate for further development.
- Guo, Bin,Guo, Shimeng,Huang, Jing,Li, Jingya,Li, Jia,Chen, Qian,Zhou, Xianli,Xie, Xin,Yang, Yushe
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p. 5780 - 5791
(2018/11/06)
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- BENZENE-FUSED 6-MEMBERED OXYGEN-CONTAINING HETEROCYCLIC DERIVATIVES OF BICYCLIC HETEROARYLS
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The invention relates to new derivatives of formula I, wherein the substituents are as defined in the specification; to processes for the preparation of such derivatives; pharmaceutical compositions comprising such derivatives; such derivatives as a medicament; such derivatives for the treatment of a proliferative disease.
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- (2R)-2-ethylchromane-2-carboxylic acids: Discovery of novel PPARα/γ dual agonists as antihyperglycemic and hypolipidemic agents
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A series of chromane-2-carboxylic acid derivatives was synthesized and evaluated for PPAR agonist activities. A structure-activity relationship was developed toward PPARα/γ dual agonism. As a result, (2R)-7-{3-[2-chloro-4-(4-fluorophenoxy)phenoxy]propoxy}
- Koyama, Hiroo,Miller, Daniel J.,Boueres, Julia K.,Desai, Ranjit C.,Jones, A. Brian,Berger, Joel P.,MacNaul, Karen L.,Kelly, Linda J.,Doebber, Thomas W.,Wu, Margaret S.,Zhou, Gaochao,Wang, Pei-Ran,Ippolito, Marc C.,Chao, Yu-Sheng,Agrawal, Arun K.,Franklin, Ronald,Heck, James V.,Wright, Samuel D.,Moller, David E.,Sahoo, Soumya P.
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p. 3255 - 3263
(2007/10/03)
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- Chroman and benzofuran derivatives as 5-hydroxytryptamine-6 ligands
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The present invention provides a compound of formula I and the use thereof for the therapeutic treatment of disorders relating to or affected by the 5-HT6 receptor.
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- Benzopyrancarboxylic acid derivatives for the treatment of diabetes and lipid disorders
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A class of benzopyrancarboxylic acid derivatives comprises compounds that are potent agonists of PPAR alpha and/or gamma, and are therefore useful in the treatment, control or prevention of non-insulin dependent diabetes mellitus (NIDDM), hyperglycemia, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, obesity, vascular restenosis, inflammation, and other PPAR alpha and/or gamma mediated diseases, disorders and conditions.
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- Benzopyrancarboxylic acid derivatives for the treatment of diabetes and lipid disorders
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A class of benzopyrancarboxylic acid derivatives comprises compounds that are potent agonists of PPAR alpha and/or gamma, and are therefore useful in the treatment, control or prevention of non-insulin dependent diabetes mellitus (NIDDM), hyperglycemia, d
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- 3,4-Dihydro-2H-1-benzopyran-2-carboxylic Acids and Related Compounds as Leukotriene Antagonists
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Evaluation of a series of 3,4-dihydro-2H-1-benzopyran-2-carboxylic acids linked to the 2-hydroxyacetophenone pharmacophore present in the standard peptidoleukotriene antagonist FPL 55712 (1) has led to the discovery of Ro 23-3544 (7), an antagonist possessing greater potency and duration of action vs LTD4 than the standard (aerosol route of administration, guinea pig bronchoconstriction model).Interestingly, this compound also potently inhibited bronchoconstriction induced by LTB4 whereas 1 did not.Attempts to establish structure-activity relationships in this series involved modifications in the 2-hydroxyacetophenone moiety, the linking chain, and the chroman system.All variations produced analogues which were either inactive or possessed reduced potency relative to acid 7.Optical resolution of 7 was achieved by two methods.Absolute configurations of the enantiomers were determined via X-ray crystallographic analyses of an intermediate as well as a salt of the S enantiomer.Although the enantiommers exhibited similar potencies in in vitro assays and in vivo when administered intravenously, significant differences were observed in the guinea pig bronchoconstriction model vs LTC4 and LTD4 when administered by the aerosol route (S antipode 15-fold more potent).The properties of 7 have been compared with several recently reported leukotriene antagonists.
- Cohen, Noal,Weber, Giuseppe,Banner, Bruce L.,Lopresti, Rocco J.,Schaer, Beatrice,et al.
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p. 1842 - 1860
(2007/10/02)
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