1227065-29-3Relevant articles and documents
Design, optimization, and biological evaluation of novel keto-benzimidazoles as potent and selective inhibitors of phosphodiesterase 10A (PDE10A)
Hu, Essa,Kunz, Roxanne K.,Chen, Ning,Rumfelt, Shannon,Siegmund, Aaron,Andrews, Kristin,Chmait, Samer,Zhao, Sharon,Davis, Carl,Chen, Hang,Lester-Zeiner, Dianna,Ma, Ji,Biorn, Christopher,Shi, Jianxia,Porter, Amy,Treanor, James,Allen, Jennifer R.
, p. 8781 - 8792 (2013/12/04)
Our development of PDE10A inhibitors began with an HTS screening hit (1) that exhibited both high p-glycoprotein (P-gp) efflux ratios in rat and human and poor metabolic stability. On the basis of cocrystal structure of 1 in human PDE10A enzyme, we designed a novel keto-benzimidazole 26 with comparable PDE10A potency devoid of efflux liabilities. On target in vivo coverage of PDE10A in rat brain was assessed using our previously reported LC-MS/MS receptor occupancy (RO) technology. Compound 26 achieved 55% RO of PDE10A at 30 mg/kg po and covered PDE10A receptors in rat brain in a dose-dependent manner. Cocrystal structure of 26 in PDE10A confirmed the binding mode of the novel scaffold. Further optimization resulted in the identification of keto-benzimidazole 34, which showed an increased in vivo efficacy of 57% RO in rats at 10 mg/kg po and an improved in vivo rat clearance and oral bioavailability.
