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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发现高度选择性、口服的基于苯并咪唑的磷酸二酯酶 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
DOI：
10.1016/j.apsb.2020.04.003
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Luo HB
中科院分区：
文献类型：
--
作者：
Yang Y;Zhang S;Zhou Q;Zhang C;Gao Y;Wang H;Li Z;Wu D;Wu Y;Huang YY;Guo L;Luo HB
为了改善溶解度和药代动力学特性，从先前合成的抑制剂a开始长期治疗肺动脉高压（PAH），研究人员致力于发现新的PDE10A抑制剂。结果，一种有效且高选择性的PDE10A抑制剂14.3 hcl（最大抑制浓度的一半），IC50 = 2.8 nmol/L, >选择性为3500倍)具有理想的溶解度和代谢稳定性，生物利用度为50%，通过有效的结合自由能预测方法得到鉴定。动物PAH研究表明，14.3盐酸[2.5 mg/kg，口服（p.o）]对PAH的改善作用与他达拉非（5.0 mg/kg, p.o）相当，验证了PDE10A抑制剂抗PAH治疗的可行性。PDE10A−14配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。获得了一种有效的高选择性PDE10A抑制剂14·3HCl （IC50 = 2.8 nmol/L，选择性>3500倍），生物利用度为50%，验证了抗pah治疗的可行性。PDE10A - 14配合物的晶体结构说明了这种结合模式，为合理设计高选择性PDE10A抑制剂提供了指导。
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. A potent and highly selective PDE10A inhibitor, 14·3HCl (IC50 = 2.8 nmol/L and >3500-folds selectivity) with a remarkable bioavailability of 50% was obtained to verify the feasibility for the anti-PAH treatment. The crystal structure of PDE10A–14 complex illustrated the binding pattern, providing a guideline for rational design of highly selective PDE10A inhibitors.
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影响因子：
3.7
作者：
Tian X;Vroom C;Ghofrani HA;Weissmann N;Bieniek E;Grimminger F;Seeger W;Schermuly RT;Pullamsetti SS
通讯作者：
Pullamsetti SS
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影响因子：
7.4
作者：
Niu, Weifen;Guo, Lei;Wong, Man Shing
通讯作者：
Wong, Man Shing
影响因子：
7.3
作者：
Varma, Manthena V. S.;Obach, R. Scott;Troutman, Matthew D.
通讯作者：
Troutman, Matthew D.
作为 PDE9 抑制剂的新型嘧啶酮衍生物的基于结构的设计、合成和生物学评价
影响因子：
14.5
作者：
Wu, Xu-Nian;Huang, Ya-Dan;Luo, Hai-Bin
通讯作者：
Luo, Hai-Bin
DOI：
10.1016/j.apsb.2018.04.003
发表时间：
2018-09
期刊：
Acta pharmaceutica Sinica. B
影响因子：
--
作者：
Zhang Z;Tang W
通讯作者：
Tang W