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

Lei Guo¹  Yi-You Huang²  Hai-Bin Luo²  Chen Zhang³  Deyan Wu³  Yuncong Yang³  Yuqi Gao³  Zhe Li³  Hao Wang³  Yinuo Wu³  Sirui Zhang³  Qian Zhou³ 

[1] School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China;Corresponding authors. Tel./fax: [phone].;School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China;

关键词: Phosphodiesterase 10A;    Inhibitor;    Benzimidazole derivatives;    Crystal structure;    Metabolic stability;    Bioavailability;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown