摘要
Optimization efforts were devoted to discover novel PDE10 A 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 PDE10 A inhibitor,14·3 HC1(half maximal inhibitory concentration,IC50=2.8 nmol/L and>3500-fold selectivity)exhibiting desirable solubility and metabolic stability with a remarkable bioavailability of50%was identified with the aid of efficient methods of binding free energy predictions.Animal PAH studies showed that the improvement offered by 14·3 HCl[2.5 mg/kg,oral administration(p.o.)]was comparable to tadalafil(5.0 mg/kg,p.o.),verifying the feasibility of PDE10 A inhibitors for the antiPAH treatment.The crystal structure of the PDE10 A-14 complex illustrates their binding pattern,which provided a guideline for rational design of highly selective PDE10 A inhibitors.
基金
supported by the National Natural Science Foundation of China(Nos.21708052,21877134,81602955,and 81703341)
Science Foundation of Guangzhou City(201904020023,China)
Fundamental Research Funds for the Central Universities(Nos.19ykpy126 and 19ykpy123,China)
China Postdoctoral Science Foundation(Nos.2019M663325 and 2019M663326)
Guangdong Province Higher Vocational Colleges&Schools Pearl River Scholar Funded Scheme(2016,China)