7bpi
The crystal structue of PDE10A complexed with 14
Structural highlights
FunctionPDE10_HUMAN Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.[1] Publication Abstract from PubMedOptimization 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 A. As a result, a potent and highly selective PDE10A inhibitor, 14.3HCl (half maximal inhibitory concentration, IC50 = 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 14.3HCl [2.5 mg/kg, oral administration (p.o.)] was comparable to tadalafil (5.0 mg/kg, p.o.), verifying the feasibility of PDE10A inhibitors for the anti-PAH treatment. The crystal structure of the PDE10A-14 complex illustrates their binding pattern, which provided a guideline for rational design of highly selective PDE10A inhibitors. Discovery of highly selective and orally available benzimidazole-based phosphodiesterase 10 inhibitors with improved solubility and pharmacokinetic properties for treatment of pulmonary arterial hypertension.,Yang Y, Zhang S, Zhou Q, Zhang C, Gao Y, Wang H, Li Z, Wu D, Wu Y, Huang YY, Guo L, Luo HB Acta Pharm Sin B. 2020 Dec;10(12):2339-2347. doi: 10.1016/j.apsb.2020.04.003., Epub 2020 Apr 18. PMID:33354505[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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