title: 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.
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.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Na-Na
authors.initials: NN
authors.lastname: Shang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China; Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599-7260, USA.
authors.forename: Yong-Xian
authors.initials: YX
authors.lastname: Shao
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Ying-Hong
authors.initials: YH
authors.lastname: Cai
authors.affiliation: Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599-7260, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Guan
authors.affiliation: Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599-7260, USA.
authors.forename: Manna
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599-7260, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Cui
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Yan-Jun
authors.initials: YJ
authors.lastname: Yu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China. Electronic address: phsbxzh@mail.sysu.edu.cn.
authors.forename: Xian-Zhang
authors.initials: XZ
authors.lastname: Bu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China; Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599-7260, USA. Electronic address: hke@med.unc.edu.
authors.forename: Hengming
authors.initials: H
authors.lastname: Ke
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China. Electronic address: luohb77@mail.sysu.edu.cn.
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Luo
mesh_terms: D018360:Crystallography, X-Ray; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D058986:Phosphodiesterase 5 Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000588599:3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno(2,3-c)pyrrol-9(2H)-one; D058986:Phosphodiesterase 5 Inhibitors; D011758:Pyrroles
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