title: Design, synthesis, and biological activity of potent and orally available G protein-coupled receptor 40 agonists.
abstract: G protein-coupled receptor 40 (GPR40) is being recently considered to be a new potential drug target for the treatment of type 2 diabetes because of its role in the enhancement of free fatty acid-regulated glucose-stimulated insulin secretion in pancreatic β-cells. We initially identified benzyloxyphenylpropanoic acid (1b) (EC(50) = 510 nM), which was designed based on the structure of free fatty acids, as a promising lead compound with GPR40 agonist activity. Chemical modification of compound 1b led to the discovery of 3-{4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid (4p) as a potent GPR40 agonist (EC(50) = 5.7 nM). Compound 4p exhibited acceptable pharmacokinetic profiles and significant glucose-lowering effects during an oral glucose tolerance test in diabetic rats. Moreover, no hypoglycemic event was observed even after administration of a high dose of compound 4p to normal fasted rats. These pharmacological results suggest that GPR40 agonists might be novel glucose-dependent insulin secretagogues with little or no risk of hypoglycemia.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85 Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan. Sasaki_Shinobu@takeda.co.jp
authors.forename: Shinobu
authors.initials: S
authors.lastname: Sasaki
authors.forename: Shuji
authors.initials: S
authors.lastname: Kitamura
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Negoro
authors.forename: Masami
authors.initials: M
authors.lastname: Suzuki
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tsujihata
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Suzuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Santou
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
authors.forename: Masataka
authors.initials: M
authors.lastname: Harada
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Makoto
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Norio
authors.initials: N
authors.lastname: Tada
authors.forename: Miyuki
authors.initials: M
authors.lastname: Funami
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Tanaka
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukatsu
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Yasuma
authors.forename: Yu
authors.initials: Y
authors.lastname: Momose
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001786:Blood Glucose / Q000032:analysis; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy; D015195:Drug Design; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C558524:3-(4-((2',6'-dimethylbiphenyl-3-yl)methoxy)-2-fluorophenyl)propanoic acid; D001713:Biphenyl Compounds; D001786:Blood Glucose; C473034:FFAR1 protein, human; D007004:Hypoglycemic Agents; D010666:Phenylpropionates; D043562:Receptors, G-Protein-Coupled