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Design, Synthesis and Structure–Activity Relationship of Functionalized Tetrahydro‐ β ‐carboline Derivatives as Novel PDE5 Inhibitors
Author(s) -
Ahmed Nermin S.,
Gary Bernard D.,
Tinsley Hethar N.,
Piazza Gary A.,
Laufer Stefan,
Abadi Ashraf H.
Publication year - 2011
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201000236
Subject(s) - chemistry , tadalafil , substituent , stereochemistry , selectivity , combinatorial chemistry , erectile dysfunction , organic chemistry , catalysis , medicine
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 (IC 50 = 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.