2019•Journal of Medicinal ChemistryOpen access
Pharmacokinetics-Driven Optimization of 4(3H)-Pyrimidinones as Phosphodiesterase Type 5 Inhibitors Leading to TPN171, a Clinical Candidate for the Treatment of Pulmonary Arterial Hypertension
Zhen Wang, Xiangrui Jiang, Xianglei Zhang, Guanghui Tian, Rulei Yang, Jianzhong Wu, Xiaoli Zou, Zheng Liu, Xiaojun Yang, Chunhui Wu, Jing Shi, Jianfeng Li, Jin Suo, Yu Wang, Rongxia Zhang, Zhijian Xu, Xudong Gong, He Yang, Weiliang Zhu, Haji Akber Aisa, Hualiang Jiang, Yechun Xu, Jingshan Shen
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Abstract
Phosphodiesterase type 5 (PDE5) inhibitors are first-line therapy for pulmonary arterial hypertension (PAH) and erectile dysfunction. As a continuing work to improve the terminal half-lives and oral bioavailabilities of our previously reported 4(3 H)-pyrimidones, a pharmacokinetics-driven optimization focusing on the terminal substituent is described. Two major congeneric series of 4(3 H)-pyrimidones, the aminosulfonylphenylpyrimidones and acylaminophenylpyrimidones, were designed, synthesized, and pharmacologically assessed in vitro and in vivo. Among them, compound 15 (TPN171) with subnanomolar potency for PDE5 and good selectivity over PDE6 was finally recognized as a potential drug candidate, and its pharmacokinetic profiles in rats and dogs are significantly improved compared to the starting compound (3). Moreover, TPN171 was proven to exert a longer lasting effect than sildenafil in animal models, providing a foundation for a once-daily oral administration for its clinical use. TPN171 is currently being investigated in a phase II clinical trial for the treatment of PAH.