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

Abstract We previously reported a novel series of 1 H -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 (0.71 μM 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, 3 H -[1,2,3]triazolo[4,5- c ]pyridine derivative 32o , with improved solubility (15.9 μM at pH6.8).