Design, Synthesis and Structure–Activity Relationship of Functionalized Tetrahydro‐β‐carboline Derivatives as Novel PDE5 Inhibitors
- 22 December 2010
- journal article
- research article
- Published by Wiley in Archiv der Pharmazie
- Vol. 344 (3), 149-157
- https://doi.org/10.1002/ardp.201000236
Abstract
Starting from tadalafil as a template, a series of functionalized tetrahydro‐β‐carboline derivatives have been prepared and identified as novel potent and selective PDE5 inhibitors. Replacing the 3,4‐methylenedioxyphenyl at position 6 of tadalafil, together with elongation of the N2‐methyl substituent and manipulation of the stereochemical aspects of the two chiral carbons led to the identification of compound XXI, a highly potent PDE5 inhibitor (IC50 = 3 nM). Compound XXI was also highly selective for PDE5 versus PDE3B, PDE4B, and PDE11A, with a selectivity index of 52 and 235 towards PDE5 rather than PDE11 with both cAMP and cGMP as substrate, respectively.Keywords
This publication has 13 references indexed in Scilit:
- Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell functionThe Journal of Experimental Medicine, 2006
- Phosphodiesterase 11 (PDE11): is it a player in human testicular function?International Journal of Impotence Research, 2005
- Suppression of cyclic GMP-specific phosphodiesterase 5 promotes apoptosis and inhibits growth in HT29 cellsJournal of Cellular Biochemistry, 2005
- High biochemical selectivity of tadalafil, sildenafil and vardenafil for human phosphodiesterase 5A1 (PDE5) over PDE11A4 suggests the absence of PDE11A4 cross-reaction in patientsInternational Journal of Impotence Research, 2004
- The Discovery of Tadalafil: A Novel and Highly Selective PDE5 Inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1‘,2‘:1,6]pyrido[3,4-b]indole-1,4-dione AnaloguesJournal of Medicinal Chemistry, 2003
- The Discovery of Tadalafil: A Novel and Highly Selective PDE5 Inhibitor. 1: 5,6,11,11a-Tetrahydro-1H-imidazo[1‘,5‘:1,6]pyrido[3,4-b]indole-1,3(2H)-dione AnaloguesJournal of Medicinal Chemistry, 2003
- Cyclic GMP Phosphodiesterases and Regulation of Smooth Muscle FunctionCirculation Research, 2003
- A Fluorescence Polarization Assay for Cyclic Nucleotide PhosphodiesterasesSLAS Discovery, 2002
- General method for the assignment of stereochemistry of 1,3-disubstituted 1,2,3,4-tetrahydro-.beta.-carbolines by carbon-13 spectroscopyJournal of the American Chemical Society, 1980
- 13C-NMR of 1,3-Disubstituted 1,2,3,4-Tetrahydro-b-carbolinesHETEROCYCLES, 1976