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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
Acta Pharmaceutica Sinica B ( IF 14.7 ) Pub Date : 2020-04-18 , DOI: 10.1016/j.apsb.2020.04.003
Yuncong Yang 1 , Sirui Zhang 1 , Qian Zhou 1 , Chen Zhang 1 , Yuqi Gao 1 , Hao Wang 1 , Zhe Li 1 , Deyan Wu 1 , Yinuo Wu 1 , Yi-You Huang 1 , Lei Guo 1 , Hai-Bin Luo 1
Affiliation  

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.



中文翻译:

发现高选择性和口服可用的苯并咪唑基磷酸二酯酶 10 抑制剂,具有改善的溶解度和药代动力学特性,用于治疗肺动脉高压

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。

更新日期:2020-04-18
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