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 hyperten-sion(PAH)starting from the previously synthesized inhibitor A.As a result,a potent and highly selective PDE10A inhibitor,14-3HC1(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 14-3HC1[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.