Journal
BIOCHEMICAL PHARMACOLOGY
Volume 89, Issue 1, Pages 86-98Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2014.02.013
Keywords
Phosphodiesterase; Guanosine 3 ',5 '-cyclic monophosphate; PDE5 inhibitor; Crystal structure; Structure-based molecular design
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Funding
- US NIH [GM59791]
- Natural Science Foundation of China [30973619, 81172931, 21103234, 81373258]
- Guangdong Natural Science Foundation [S2011030003190]
- Guangdong Science Foundation [2012A080201007]
- Guangdong Provincial Key Laboratory of Construction Foundation [2011A060901014]
- Fundamental Research Funds for the Central Universities [11ykzd05, 09ykpy66]
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Phosphodiesterase-5 (PDE5) inhibitors have been approved for the treatment of erectile dysfunction and pulmonary hypertension, but enthusiasm on discovery of PDE5 inhibitors continues for their potential new applications. Reported here is discovery of a series of new PDE5 inhibitors by structure-based design, molecular docking, chemical synthesis, and enzymatic characterization. The best compound, 3(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one (57), has an IC50 of 17 nM against the PDE5 catalytic domain and good selectivity over other PDE families. The crystal structure of the PDE5 catalytic domain in complex with 57 was determined at 2 angstrom resolution and showed that 57 occupies the same pocket as other PDE5 inhibitors, but has a different binding pattern in detail. On the basis of the binding pattern of 57, a novel scaffold can be proposed as a candidate of PDE inhibitors. (C) 2014 Elsevier Inc. All rights reserved.
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