title: Discovery of phenylpropanoic acid derivatives containing polar functionalities as potent and orally bioavailable G protein-coupled receptor 40 agonists for the treatment of type 2 diabetes.
abstract: As part of a program to identify potent GPR40 agonists with drug-like properties suitable for clinical development, the incorporation of polar substituents was explored with the intention of decreasing the lipophilicity of our recently disclosed phenylpropanoic acid derivative 1. This incorporation would allow us to mitigate the cytotoxicity issues observed with compound 1 and enable us to move away from the multifunctional free fatty acid-like structure. Substitutions on the 2',6'-dimethylbiphenyl ring were initially undertaken, which revealed the feasibility of introducing polar functionalities at the biphenyl 4'-position. Further optimization of this position and the linker led to the discovery of several 4'-alkoxybiphenyl derivatives, which showed potent GPR40 agonist activities with the best balance in terms of improved cytotoxicity profiles and favorable pharmacokinetic properties. Among them, 3-{2-fluoro-4-[({4'-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2',6'-dimethylbiphenyl-3-yl}methyl)amino]phenyl}propanoic acid (35) exhibited a robust plasma glucose-lowering effect and insulinotropic action during an oral glucose tolerance test in rats with impaired glucose tolerance.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1 Muraoka-higashi, 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Mikami_Satoshi@takeda.co.jp
authors.forename: Satoshi
authors.initials: S
authors.lastname: Mikami
authors.forename: Shuji
authors.initials: S
authors.lastname: Kitamura
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Negoro
authors.forename: Shinobu
authors.initials: S
authors.lastname: Sasaki
authors.forename: Masami
authors.initials: M
authors.lastname: Suzuki
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tsujihata
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Ryo
authors.initials: R
authors.lastname: Ito
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Suzuki
authors.forename: Junichi
authors.initials: J
authors.lastname: Miyazaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Santou
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
authors.forename: Miyuki
authors.initials: M
authors.lastname: Funami
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Tanaka
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Yasuma
authors.forename: Yu
authors.initials: Y
authors.lastname: Momose
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D006224:Cricetinae; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005260:Female; D018149:Glucose Intolerance / Q000188:drug therapy; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D008297:Male; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C573555:3-(2-fluoro-4-(((4'-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2',6'-dimethylbiphenyl-3-yl)methyl)amino)phenyl)propanoic acid; D003499:Cyclic S-Oxides; C473034:FFAR1 protein, human; C473035:G-protein-coupled receptor 40, rat; D007004:Hypoglycemic Agents; D010666:Phenylpropionates; D043562:Receptors, G-Protein-Coupled; D020169:Caspases; D002118:Calcium