Design, Optimization, and Biological Evaluation of Novel Keto-Benzimidazoles as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A)
Citations Over TimeTop 10% of 2013 papers
Abstract
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.
Related Papers
- → Increased social interaction in mice deficient of the striatal medium spiny neuron‐specific phosphodiesterase 10A2(2007)93 cited
- → Alterations in gene regulation following inhibition of the striatum-enriched phosphodiesterase, PDE10A(2009)51 cited
- → Phosphodiesterase 10A inhibitors as a novel therapeutic approach for schizophrenia(2007)19 cited
- → Phosphodiesterases Expression during Murine Cardiac Development(2021)10 cited
- → cGMP-Binding Phosphodiesterase: Novel Effects of cGMP Binding on the Interaction Between Functional Domains in the Enzyme(1990)