7BPI

The crystal structue of PDE10A complexed with 14

Summary for 7BPI

• Entry DOI: 10.2210/pdb7bpi/pdb
• Descriptor: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: pde10a inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 75276.95

Authors

Yang, Y.,Zhang, S.,Zhou, Q.,Huang, Y.-Y.,Guo, L.,Luo, H.-B. (deposition date: 2020-03-22, release date: 2021-01-27, Last modification date: 2023-11-29)

Primary citation

Yang, Y.,Zhang, S.,Zhou, Q.,Zhang, C.,Gao, Y.,Wang, H.,Li, Z.,Wu, D.,Wu, Y.,Huang, Y.Y.,Guo, L.,Luo, H.B.
Discovery of highly selective and orally available benzimidazole-based phosphodiesterase 10 inhibitors with improved solubility and pharmacokinetic properties for treatment of pulmonary arterial hypertension.
Acta Pharm Sin B, 10:2339-2347, 2020

PubMed Abstract: Optimization efforts were devoted to discover novel PDE10A inhibitors in order to improve solubility and pharmacokinetics properties for a long-term therapy against pulmonary arterial hypertension (PAH) starting from the previously synthesized inhibitor . As a result, a potent and highly selective PDE10A inhibitor, 3HCl (half maximal inhibitory concentration, IC = 2.8 nmol/L and 3500-fold selectivity) exhibiting desirable solubility and metabolic stability with a remarkable bioavailability of 50% was identified with the aid of efficient methods of binding free energy predictions. Animal PAH studies showed that the improvement offered by 3HCl [2.5 mg/kg, oral administration (.)] was comparable to tadalafil (5.0 mg/kg, .), verifying the feasibility of PDE10A inhibitors for the anti-PAH treatment. The crystal structure of the PDE10A- complex illustrates their binding pattern, which provided a guideline for rational design of highly selective PDE10A inhibitors.

PubMed: 33354505
DOI: 10.1016/j.apsb.2020.04.003

Experimental method

X-RAY DIFFRACTION (2.40008632403 Å)