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Discovery of highly selective and orally available benzimidazole-based phosphodiesterase 10 inhibitors with improved solubility and pharmacokinetic properties for treatment of pulmonary arterial hypertension

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 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. Graphical abstract A potent and highly selective PDE10A inhibitor, 14·3HCl (IC50 = 2.8 nmol/L and >3500-folds selectivity) with a remarkable bioavailability of 50% was obtained to verify the feasibility for the anti-PAH treatment. The crystal structure of PDE10A–14 complex illustrated the binding pattern, providing a guideline for rational design of highly selective PDE10A inhibitors.Image 1

SUBMITTER: Yang Y

PROVIDER: S-EPMC7745062 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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