Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 62, Issue 10, Pages 4979-4990Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b00123
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Funding
- Strategic Priority Research Program of Chinese Academy of Sciences [XDA12040103]
- National Key R&D Program of China [2016YFA0502301]
- Scientific and Technological Innovation Program of Science and Technology Commission of Shanghai Municipality [16431900600]
- National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China [2018ZX09711002]
- National Natural Science Foundation of China [81422047]
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Phosphodiesterase type 5 (PDES) 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(3H)-pyrimidones, a pharmacokinetics-driven optimization focusing on the terminal substituent is described. Two major congeneric series of 4(3H)-pyrimidones, the aminosulfonylphenylpyrimidones and acylamino-phenylpyrimidones, 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.
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