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

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

doi:10.1021/acs.jmedchem.7b00523

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

J Med Chem. 2017 Aug 10;60(15):6622-6637. doi: 10.1021/acs.jmedchem.7b00523. Epub 2017 Jul 25.

Authors

Deyan Wu¹, Tianhua Zhang¹, Yiping Chen¹, Yadan Huang¹, Haiju Geng¹, Yanfa Yu¹, Chen Zhang¹, Zengwei Lai¹, Yinuo Wu¹, Xiaolei Guo², Jianwen Chen¹, Hai-Bin Luo^{1

3}

Affiliations

¹ School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou 510006, P. R. China.
² Infinitus (China) Co. Ltd. , Guangzhou 510663, China.
³ Collaborative Innovation Center of High Performance Computing, National University of Defense Technology , Changsha 410073, China.

PMID: 28686445
DOI: 10.1021/acs.jmedchem.7b00523

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CHO Cells
Catalytic Domain
Chromones / administration & dosage
Chromones / chemical synthesis
Chromones / pharmacokinetics
Chromones / therapeutic use*
Cricetulus
Cytochrome P-450 CYP1A2 Inhibitors / administration & dosage
Cytochrome P-450 CYP1A2 Inhibitors / chemical synthesis
Cytochrome P-450 CYP1A2 Inhibitors / pharmacokinetics
Cytochrome P-450 CYP1A2 Inhibitors / therapeutic use
Drug Stability
ERG1 Potassium Channel / antagonists & inhibitors
Female
Humans
Hypertension, Pulmonary / drug therapy*
Male
Mice
Microsomes, Liver / metabolism
Molecular Docking Simulation
Molecular Dynamics Simulation
Phosphodiesterase 5 Inhibitors / administration & dosage
Phosphodiesterase 5 Inhibitors / chemical synthesis
Phosphodiesterase 5 Inhibitors / pharmacokinetics
Phosphodiesterase 5 Inhibitors / therapeutic use*
Pyrroles / administration & dosage
Pyrroles / chemical synthesis
Pyrroles / pharmacokinetics
Pyrroles / therapeutic use*
Rats, Sprague-Dawley
Rats, Wistar
Sildenafil Citrate / pharmacology
Structure-Activity Relationship

Substances

3-(benzo(d)(1,3)dioxol-5-ylmethyl)-1-(thiazol-2-yl)chromeno(2,3-c)pyrrol-9(2H)-one
Chromones
Cytochrome P-450 CYP1A2 Inhibitors
ERG1 Potassium Channel
KCNH2 protein, human
Phosphodiesterase 5 Inhibitors
Pyrroles
Sildenafil Citrate