Optimization of Chromeno[2,3‑<i>c</i>]pyrrol-9(2<i>H</i>)‑ones as Highly Potent, Selective, and Orally Bioavailable PDE5 Inhibitors: Structure–Activity Relationship, X‑ray Crystal Structure, and Pharmacodynamic Effect on Pulmonary Arterial Hypertension
dataset
posted on 2018-08-27, 00:00 authored by Deyan Wu, Yadan Huang, Yiping Chen, Yi-You Huang, Haiju Geng, Tianhua Zhang, Chen Zhang, Zhe Li, Lei Guo, Jianwen Chen, Hai-Bin LuoTo
further explore the structure–activity relationship around
the chromeno[2,3-<i>c</i>]pyrrol-9(2<i>H</i>)-one scaffold, 19 derivatives as inhibitors against PDE5 were discovered.
The most potent inhibitor <b>3</b> has an IC<sub>50</sub> of
0.32 nM with remarkable selectivity and druglike profile. Oral administration
of <b>3</b> (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.
