Journal
ARCHIV DER PHARMAZIE
Volume 344, Issue 3, Pages 149-157Publisher
WILEY-BLACKWELL
DOI: 10.1002/ardp.201000236
Keywords
beta-Carbolines; PDE5 inhibitors; SAR; Synthesis; Tadalafil
Funding
- German University
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Starting from tadalafil as a template, a series of functionalized tetrahydro-beta-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.
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