Optimization of a novel series of potent and orally bioavailable GPR119 agonists

  • Bioorg Med Chem Lett. 2017 Aug 1;27(15):3249-3253. doi: 10.1016/j.bmcl.2017.06.034.
Tomoaki Koshizawa  1 ,  Toshiharu Morimoto  2 ,  Gen Watanabe  2 ,  Toshiaki Watanabe  2 ,  Nao Yamasaki  2 ,  Yoshikazu Sawada  2 ,  Tomoaki Fukuda  2 ,  Ayumu Okuda  2 ,  Kimiyuki Shibuya  2 ,  Tadaaki Ohgiya  2
Affiliations
  • 1. Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., LTD., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan. Electronic address: [email protected].
  • 2. Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., LTD., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
PMID: 28648463 DOI: 10.1016/j.bmcl.2017.06.034
Abstract

We describe the discovery and optimization of a novel series of furo[3,2-d]pyrimidines as G protein-coupled receptor 119 agonists. Agonistic activity of 4 (EC50=129nM) was improved by replacing the intramolecular hydrogen bond between the fluorine atom and the aniline hydrogen in the head moiety with a covalent C-C bond to enhance conformational restriction, which consequently gave a lead compound 12 (EC50=53nM). Optimized compound 26, which was identified by the further optimization of 12, exhibited potent activity (EC50=42nM) with improved clearance in liver microsomes and induced a 33% reduction in blood glucose area under the curve at a dose of 10mg/kg in an oral glucose tolerance test in C57BL/6N mice.

Keywords
Furo[3,2-d]pyrimidine; GPR119 agonists; Intramolecular hydrogen bond; Restricted conformation; Type 2 diabetes mellitus.
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