Discovery of 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one as a phosphodiesterase-5 inhibitor and its complex crystal structure

Biochem Pharmacol. 2014 May 1;89(1):86-98. doi: 10.1016/j.bcp.2014.02.013. Epub 2014 Feb 22.

Abstract

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 2Å 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.

Keywords: 3-(4-(tert-Butoxy)benzyl)-1-phenylchromeno[2,3-c]pyrrol-9(2H)-one (ACP43; 3-(4-Hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one (ACP57; 3-(4-Hydroxybenzyl)-1-phenylchromeno[2,3-c]pyrrol-9(2H)-one (ACP61; 3-(4-Hydroxybenzyl)-2-methyl-1-phenylchromeno[2,3-c]pyrrol-9(2H)-one (ACP62; 3-(9-Oxo-1-phenyl-2,9-dihydrochromeno[2,3-c]pyrrol-3-yl)propanoic acid (ACP52; 3-Benzyl-1-phenylchromeno[2,3-c]pyrrol-9(2H)-one (ACP42; Crystal structure; Guanosine 3′,5′-cyclic monophosphate; PDE5 inhibitor; Phosphodiesterase; PubChem CID: 49784789); PubChem CID: 54770534); PubChem CID: 54770536); PubChem CID: 71738344); PubChem CID: 71738345); PubChem CID: 71765666); PubChem CID: 72725677); Structure-based molecular design; tert-Butyl-2-(9-oxo-1-phenyl-2,9-dihydrochromeno[2,3-c]pyrrol-3-yl)acetate (ACP37.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Inhibitory Concentration 50
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Models, Molecular
  • Phosphodiesterase 5 Inhibitors / chemistry
  • Phosphodiesterase 5 Inhibitors / pharmacology*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*

Substances

  • 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno(2,3-c)pyrrol-9(2H)-one
  • Phosphodiesterase 5 Inhibitors
  • Pyrroles