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Publication Abstract from PubMed

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. Based on co-crystal 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. Co-crystal 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.

Design, Optimization, and Biological Evaluation of Novel Keto-Benzimidazoles as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A).,Hu E, Kunz RK, Chen N, Rumfelt S, Siegmund A, Andrews K, Chmait S, Zhao S, Davis C, Chen H, Lester-Zeiner D, Ma J, Biorn C, Shi J, Porter A, Treanor J, Allen JR J Med Chem. 2013 Oct 8. PMID:24102193^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.