title: Identification of fused-ring alkanoic acids with improved pharmacokinetic profiles that act as G protein-coupled receptor 40/free fatty acid receptor 1 agonists.
abstract: The G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. We previously identified phenylpropanoic acid derivative 1 (3-{4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid) as a potent and orally available GPR40/FFA1 agonist; however, 1 exhibited high clearance and low oral bioavailability, which was likely due to its susceptibility to β-oxidation at the phenylpropanoic acid moiety. To identify long-acting compounds, we attempted to block the metabolically labile sites at the phenylpropanoic acid moiety by introducing a fused-ring structure. Various fused-ring alkanoic acids with potent GPR40/FFA1 activities and good PK profiles were produced. Further optimizations of the lipophilic portion and the acidic moiety led to the discovery of dihydrobenzofuran derivative 53 ((6-{[4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}-2,3-dihydro-1-benzofuran-3-yl)acetic acid), which acted as a GPR40/FFA1 agonist with in vivo efficacy during an oral glucose tolerance test (OGTT) in rats with impaired glucose tolerance.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Negoro_Nobuyuki@takeda.co.jp
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Negoro
authors.forename: Shinobu
authors.initials: S
authors.lastname: Sasaki
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ito
authors.forename: Shuji
authors.initials: S
authors.lastname: Kitamura
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tsujihata
authors.forename: Ryo
authors.initials: R
authors.lastname: Ito
authors.forename: Masami
authors.initials: M
authors.lastname: Suzuki
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
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: Tomoyuki
authors.initials: T
authors.lastname: Odani
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: D000085:Acetates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000144:Acids, Acyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D018149:Glucose Intolerance / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood* / Q000378:metabolism; D000078790:Insulin Secretion; D008958:Models, Molecular; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013045:Species Specificity
chemical_list: C572349:(6-((4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydro-1-benzofuran-3-yl)acetic acid; D000085:Acetates; D000144:Acids, Acyclic; D001572:Benzofurans; C473034:FFAR1 protein, human; C473035:G-protein-coupled receptor 40, rat; D007328:Insulin; D043562:Receptors, G-Protein-Coupled