4MUW

Crystal Structure of PDE10A with Novel Keto-Benzimidazole Inhibitor

Summary for 4MUW

• Entry DOI: 10.2210/pdb4muw/pdb
• Descriptor: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, SULFATE ION, ... (6 entities in total)
• Functional Keywords: pde10a, phosphodiesterase 10a, inhibitors, keto-benzimidazoles, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q9Y233
• Total number of polymer chains: 2
• Total formula weight: 83834.34

Authors

Chmait, S.,Jordan, S. (deposition date: 2013-09-23, release date: 2013-10-23, Last modification date: 2024-10-30)

Primary citation

Hu, E.,Kunz, R.K.,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, J.R.
Design, Optimization, and Biological Evaluation of Novel Keto-Benzimidazoles as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A).
J.Med.Chem., 56:8781-8792, 2013

PubMed 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.

PubMed: 24102193
DOI: 10.1021/jm401234w

Experimental method

X-RAY DIFFRACTION (2.639 Å)