2. Academic Validation
  3. 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

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

  • J Med Chem. 2012 Apr 26;55(8):3960-74. doi: 10.1021/jm300170m.
Nobuyuki Negoro 1,  Shinobu Sasaki,  Satoshi Mikami,  Masahiro Ito,  Yoshiyuki Tsujihata,  Ryo Ito,  Masami Suzuki,  Koji Takeuchi,  Nobuhiro Suzuki,  Junichi Miyazaki,  Takashi Santou,  Tomoyuki Odani,  Naoyuki Kanzaki,  Miyuki Funami,  Akio Morohashi,  Masami Nonaka,  Shinichiro Matsunaga,  Tsuneo Yasuma,  Yu Momose
Affiliations

Affiliation

  • 1 Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
PMID: 22490067 DOI: 10.1021/jm300170m
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.

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