Discovery of a novel olefin derivative as a highly potent and selective acetyl-CoA carboxylase 2 inhibitor with in vivo efficacy

  • Bioorg Med Chem Lett. 2018 Aug 1;28(14):2498-2503. doi: 10.1016/j.bmcl.2018.05.055.
Yuji Nishiura  1 ,  Akira Matsumura  2 ,  Naotake Kobayashi  2 ,  Atsuyuki Shimazaki  3 ,  Shingo Sakamoto  4 ,  Naohisa Kitade  4 ,  Yutaka Tonomura  4 ,  Akira Ino  2 ,  Takayuki Okuno  2
Affiliations
  • 1. Medicinal Research Laboratory, Shionogi & Co., Ltd, 1-1, Futabacho 3-chome, Toyonaka, Osaka 561-0825, Japan. Electronic address: [email protected].
  • 2. Medicinal Research Laboratory, Shionogi & Co., Ltd, 1-1, Futabacho 3-chome, Toyonaka, Osaka 561-0825, Japan.
  • 3. Drug Discovery & Disease Research Developmental Research Laboratory, Shionogi & Co., Ltd, 1-1, Futabacho 3-chome, Toyonaka, Osaka 561-0825, Japan.
  • 4. Research Laboratory for Development, Shionogi & Co., Ltd, 1-1, Futabacho 3-chome, Toyonaka, Osaka 561-0825, Japan.
PMID: 29903660 DOI: 10.1016/j.bmcl.2018.05.055
Abstract

Novel Acetyl-CoA Carboxylase 2 (ACC2) selective inhibitors were identified by the conversion of the alkyne unit of A-908292 to the olefin linker. Modification of the center and left part of the lead compound 1b improved the ACC2 inhibitory activity and CYP450 inhibition profile, and afforded a highly selective ACC2 inhibitor 2e which showed in vivo efficacy in C57BL/6 mice.

Keywords
ACC2 inhibitor; Benzothiazole; Olefin; Type 2 diabetes.
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