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

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

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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 hyperten-sion(PAH)starting from the previously synthesized inhibitor A.As a result,a potent and highly selective PDE10A inhibitor,14-3HC1(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 14-3HC1[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.

Phosphodiesterase 10AInhibitorBenzimidazole derivativesCrystal structureMetabolic stabilityBioavailabilityPulmonary arterial hypertension

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

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School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China

National Natural Science Foun-dation of ChinaNational Natural Science Foun-dation of ChinaNational Natural Science Foun-dation of ChinaNational Natural Science Foun-dation of ChinaNational Natural Science Foun-dation of ChinaScience Foundation of Guangzhou CityScience Foundation of Guangzhou CityFundamental Research Funds for the Central UniversitiesFundamental Research Funds for the Central UniversitiesFundamental Research Funds for the Central UniversitiesChina Postdoctoral Science FoundationChina Postdoctoral Science FoundationGuangdong Province Higher Vocational Colleges& Schools Pearl River Scholar Funded SchemeGuangdong Province Higher Vocational Colleges& Schools Pearl River Scholar Funded Scheme

Nos.21708052218771348160295581703341201904020023ChinaNos.19ykpy12619ykpy123ChinaNos.2019M6633252019M6633262016China

2020

药学学报(英文版)

药学学报(英文版)

CSTPCDCSCDSCI
ISSN：
年,卷(期)：2020.10(12)
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