The Discovery, Preclinical, and Early Clinical Development of Potent and Selective GPR40 Agonists for the Treatment of Type 2 Diabetes Mellitus (LY2881835, LY2922083, and LY2922470).

Autor: Hamdouchi C; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Kahl SD; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Patel Lewis A; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Cardona GR; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Zink RW; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Chen K; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Eessalu TE; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Ficorilli JV; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Marcelo MC; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Otto KA; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Wilbur KL; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Lineswala JP; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Piper JL; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Coffey DS; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Sweetana SA; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Haas JV; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Brooks DA; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Pratt EJ; Eli Lilly and Company , 237994 Singapore., Belin RM; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Deeg MA; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Ma X; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Cannady EA; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Johnson JT; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Yumibe NP; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Chen Q; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Maiti P; Jubilant Biosys Research Center , 560 022 Bangalore, India., Montrose-Rafizadeh C; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Chen Y; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States., Reifel Miller A; Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2016 Dec 22; Vol. 59 (24), pp. 10891-10916. Date of Electronic Publication: 2016 Nov 11.
DOI: 10.1021/acs.jmedchem.6b00892
Abstrakt: The G protein-coupled receptor 40 (GPR40) also known as free fatty acid receptor 1 (FFAR1) is highly expressed in pancreatic, islet β-cells and responds to endogenous fatty acids, resulting in amplification of insulin secretion only in the presence of elevated glucose levels. Hypothesis driven structural modifications to endogenous FFAs, focused on breaking planarity and reducing lipophilicity, led to the identification of spiropiperidine and tetrahydroquinoline acid derivatives as GPR40 agonists with unique pharmacology, selectivity, and pharmacokinetic properties. Compounds 1 (LY2881835), 2 (LY2922083), and 3 (LY2922470) demonstrated potent, efficacious, and durable dose-dependent reductions in glucose levels along with significant increases in insulin and GLP-1 secretion during preclinical testing. A clinical study with 3 administered to subjects with T2DM provided proof of concept of 3 as a potential glucose-lowering therapy. This manuscript summarizes the scientific rationale, medicinal chemistry, preclinical, and early development data of this new class of GPR40 agonists.
Databáze: MEDLINE
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