Novel 3H-[1,2,3]triazolo[4,5-c]pyridine derivatives as GPR119 agonists: Synthesis and structure-activity/solubility relationships

Publication date: 15 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 16
Author(s): Daisuke Matsuda, Yohei Kobashi, Ayako Mikami, Madoka Kawamura, Fumiyasu Shiozawa, Kenichi Kawabe, Makoto Hamada, Shinichi Nishimoto, Kayo Kimura, Masako Miyoshi, Noriko Takayama, Hiroyuki Kakinuma, Norikazu Ohtake
We previously reported a novel series of 1H-pyrazolo[3,4-c]pyridine derivatives and the identification of compound 4b as a highly potent GPR119 agonist. However, the advancement of preclinical evaluations of compound 4b is expected to be difficult because of the compound's significantly poor aqueous solubility (0.71μM at pH6.8). In this article, we describe the further optimization of compound 4b focusing on the improvement of its aqueous solubility. Optimization of the central spacer, left-hand aryl group and right-hand piperidine N-capping group led to the identification of a potent GPR119 agonist, 3H-[1,2,3]triazolo[4,5-c]pyridine derivative 32o, with improved solubility (15.9μM at pH6.8).

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