title: Optimization of (2,3-dihydro-1-benzofuran-3-yl)acetic acids: discovery of a non-free fatty acid-like, highly bioavailable G protein-coupled receptor 40/free fatty acid receptor 1 agonist as a glucose-dependent insulinotropic agent.
abstract: G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) is a free fatty acid (FFA) receptor that mediates FFA-amplified glucose-stimulated insulin secretion in pancreatic β-cells. We previously identified (2,3-dihydro-1-benzofuran-3-yl)acetic acid derivative 2 as a candidate, but it had relatively high lipophilicity. Adding a polar functional group on 2 yielded several compounds with lower lipophilicity and little effect on caspase-3/7 activity at 30 μM (a marker of toxicity in human HepG2 hepatocytes). Three optimized compounds showed promising pharmacokinetic profiles with good in vivo effects. Of these, compound 16 had the lowest lipophilicity. Metabolic analysis of 16 showed a long-acting PK profile due to high resistance to β-oxidation. Oral administration of 16 significantly reduced plasma glucose excursion and increased insulin secretion during an OGTT in type 2 diabetic rats. Compound 16 (TAK-875) is being evaluated in human clinical trials for the treatment of type 2 diabetes.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Negoro
authors.forename: Shinobu
authors.initials: S
authors.lastname: Sasaki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Mikami
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ito
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: Akio
authors.initials: A
authors.lastname: Morohashi
authors.forename: Masami
authors.initials: M
authors.lastname: Nonaka
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Matsunaga
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Yasuma
authors.forename: Yu
authors.initials: Y
authors.lastname: Momose
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000187:drug effects; D013237:Stereoisomerism; D013450:Sulfones / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D001572:Benzofurans; C473034:FFAR1 protein, human; C473035:G-protein-coupled receptor 40, rat; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; C557331:TAK-875; D005947:Glucose