Discovery and Optimization of Chromeno[2,3-c]pyrrol-9(2H)-ones as Novel Selective and Orally Bioavailable Phosphodiesterase 5 Inhibitors for the Treatment of Pulmonary Arterial Hypertension

作者：Wu, Deyan; Zhang, Tianhua; Chen, Yiping; Huang, Yadan; Geng, Haiju; Yu, Yanfa; Zhang, Chen; Lai, Zengwei; Wu, Yinuo; Guo, Xiaolei; Chen, Jianwen^*; Luo, Hai-Bin^*

来源：Journal of Medicinal Chemistry, 2017, 60(15): 6622-6637.

DOI：10.1021/acs.jmedchem.7b00523

• ERECTILE DYSFUNCTION
• PDE5 INHIBITORS
• DESIGN
• PHARMACOKINETICS
• SILDENAFIL
• EXPRESSION
• TADALAFIL
• THERAPY
• POTENT
• MOUSE

Phosphodiesterase 5 (PDE5) inhibitors have been used as clinical agents to treat erectile dysfunction and pulmonary arterial hypertension (PAH). Herein, we detail the discovery of a novel series of chromeno[2,3-c]pyrrol-9(2H)-one derivatives as selective and orally bioavailable inhibitors against phosphodiesterase 5. Medicinal chemistry optimization resulted in 2, which exhibits a desirable inhibitory potency of 5.6 nM with remarkable selectivity as well as excellent pharmacokinetic properties and an oral bioavailability of 63.4%. In addition, oral administration of 2 at a dose of 5.0 mg/kg caused better pharmacodynamics effects on both mPAP (mean pulmonary artery pressure) and RVHI (index of right ventricle hypertrophy) than sildenafil citrate at a dose of 10.0 mg/kg. These activities along with its reasonable druglike properties, such as human liver microsomal stability, cytochrome inhibition, hERG inhibition, and pharmacological safety, indicate that 2 is a potential candidate for the treatment of PAH.

• 出版日期2017-8-10
• 单位中山大学; 中国人民解放军国防科学技术大学