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

作     者：Yuncong Yangy Sirui Zhangy Qian Zhouy Chen Zhang Yuqi Gao Hao Wang Zhe Li Deyan Wu Yinuo Wu Yi-You Huang Lei Guo Hai-Bin Luo Yuncong Yang;Sirui Zhang;Qian Zhou;Chen Zhang;Yuqi Gao;Hao Wang;Zhe Li;Deyan Wu;Yinuo Wu;Yi-You Huang;Lei Guo;Hai-Bin Luo

作者机构：School of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2020年第10卷第12期

页      面：2339-2347页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1004[医学-公共卫生与预防医学(可授医学、理学学位)] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学] 

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) 

主　　题：Phosphodiesterase 10A Inhibitor Benzimidazole derivatives Crystal structure Metabolic stability Bioavailability Pulmonary arterial hypertension 

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 result,a potent and highly selective PDE10 A inhibitor,14·3 HC1(half maximal inhibitory concentration,IC50=2.8 nmol/L and3500-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 *** 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 *** 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.