Optimization of Chromeno[2,3- c]pyrrol-9(2 H)-ones as Highly Potent, Selective, and Orally Bioavailable PDE5 Inhibitors: Structure-Activity Relationship, X-ray Crystal Structure, and Pharmacodynamic Effect on Pulmonary Arterial Hypertension

  • J Med Chem. 2018 Sep 27;61(18):8468-8473. doi: 10.1021/acs.jmedchem.8b01209.
Deyan Wu  1 ,  Yadan Huang  1 ,  Yiping Chen  1 ,  Yi-You Huang  1 ,  Haiju Geng  1 ,  Tianhua Zhang  1 ,  Chen Zhang  1 ,  Zhe Li  1 ,  Lei Guo  1 ,  Jianwen Chen  1 ,  Hai-Bin Luo  1
Affiliations
  • 1. School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou 510006 , P. R. China.
PMID: 30148362 DOI: 10.1021/acs.jmedchem.8b01209
Abstract

To further explore the structure-activity relationship around the chromeno[2,3- c]pyrrol-9(2 H)-one scaffold, 19 derivatives as inhibitors against PDE5 were discovered. The most potent inhibitor 3 has an IC50 of 0.32 nM with remarkable selectivity and druglike profile. Oral administration of 3 (1.25 mg/kg) caused comparable therapeutic effects to sildenafil (10.0 mg/kg) against pulmonary arterial hypertension. Further, different binding patterns from sildenafil were revealed in cocrystal structures, which provide structural templates for discovery of highly potent PDE5 inhibitors.

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