Original articles
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. Discovery of highly selective and orally available benzimidazole-based phosphodiesterase 10 inhibitors with improved solubility and pharmacokinetic properties for treatment of pulmonary arterial hypertension[J]. Acta Pharmaceutica Sinica B, 2020, 10(12): 2339-2347

Discovery of highly selective and orally available benzimidazole-based phosphodiesterase 10 inhibitors with improved solubility and pharmacokinetic properties for treatment of pulmonary arterial hypertension
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
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
Abstract:
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 Z 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 antiPAH 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.
Key words:    Phosphodiesterase 10A    Inhibitor    Benzimidazole derivatives    Crystal structure    Metabolic stability    Bioavailability    Pulmonary arterial hypertension   
Received: 2019-12-02     Revised: 2020-03-23
DOI: 10.1016/j.apsb.2020.04.003
Funds: This work was 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).
Corresponding author: Yi-You Huang, Lei Guo, Hai-Bin Luo, huangyy287@mail.sysu.edu.cn;guolei7@mail.sysu.edu.cn;luohb77@mail.sysu.edu.cn     Email:huangyy287@mail.sysu.edu.cn;guolei7@mail.sysu.edu.cn;luohb77@mail.sysu.edu.cn
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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

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