title: 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).
abstract: 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.
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Chafiq
authors.initials: C
authors.lastname: Hamdouchi
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Kahl
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Anjana
authors.initials: A
authors.lastname: Patel Lewis
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Guemalli R
authors.initials: GR
authors.lastname: Cardona
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Zink
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Keyue
authors.initials: K
authors.lastname: Chen
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Eessalu
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: James V
authors.initials: JV
authors.lastname: Ficorilli
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Marialuisa C
authors.initials: MC
authors.lastname: Marcelo
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Otto
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Wilbur
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Jayana P
authors.initials: JP
authors.lastname: Lineswala
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Jared L
authors.initials: JL
authors.lastname: Piper
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: D Scott
authors.initials: DS
authors.lastname: Coffey
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Sweetana
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Haas
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Dawn A
authors.initials: DA
authors.lastname: Brooks
authors.affiliation: Eli Lilly and Company , 237994 Singapore.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Pratt
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Belin
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Deeg
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Xiaosu
authors.initials: X
authors.lastname: Ma
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Cannady
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Johnson
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Yumibe
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Jubilant Biosys Research Center , 560 022 Bangalore, India.
authors.forename: Pranab
authors.initials: P
authors.lastname: Maiti
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Chahrzad
authors.initials: C
authors.lastname: Montrose-Rafizadeh
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.
authors.forename: Anne
authors.initials: A
authors.lastname: Reifel Miller
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005951:Glucose Tolerance Test; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C473034:FFAR1 protein, human; D007004:Hypoglycemic Agents; C000614377:LY2881835; C000620332:LY2922083; C000620333:LY2922470; D010880:Piperidines; D043562:Receptors, G-Protein-Coupled; D013141:Spiro Compounds