Optimization of Chromeno[2,3‑c]pyrrol-9(2H)‑ones as Highly Potent, Selective, and Orally Bioavailable PDE5 Inhibitors: Structure–Activity Relationship, X‑ray Crystal Structure, and Pharmacodynamic Effect on Pulmonary Arterial Hypertension
2018-08-27T00:00:00Z (GMT)
by
To
further explore the structure–activity relationship around
the chromeno[2,3-c]pyrrol-9(2H)-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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