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.

优化工作致力于发现新型 PDE10A 抑制剂，以提高溶解度和药代动力学特性，以从先前合成的抑制剂A开始长期治疗肺动脉高压 (PAH) 。结果，鉴定出一种有效且高度选择性的 PDE10A 抑制剂14· 3HCl（半数最大抑制浓度，IC ₅₀  = 2.8 nmol/L 和> 3500 倍选择性），具有理想的溶解度和代谢稳定性，生物利用度高达 50%借助结合自由能预测的有效方法。动物 PAH 研究表明14· 3HCl [2.5 mg/kg, 口服给药 ( po.)] 与他达拉非 (5.0 mg/kg, po .) 相当，验证了 PDE10A 抑制剂用于抗 PAH 治疗的可行性。PDE10A- 14复合物的晶体结构说明了它们的结合模式，为合理设计高选择性 PDE10A 抑制剂提供了指导。