Journal
SCIENTIA PHARMACEUTICA
Volume 84, Issue 3, Pages 428-446Publisher
MDPI
DOI: 10.3390/scipharm84030428
Keywords
Terahydro-beta-carboline; phosphodiesterase 5 inhibitors; stereochemistry; structure-based design
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Funding
- Faculty of Postgraduate Studies, German University in Cairo, Egypt
- National Institutes of Health Grants [1R01CA131378, 1R01CA148817, 1R01CA15538]
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Tadalafil is a clinically approved phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction and pulmonary arterial hypertension. It contains two chiral carbons, and the marketed isomer is the 6R, 12aR isomer with a methyl substituent on the terminal nitrogen of the piperazinedione ring. In this report, tadalafil analogues with an extended hydrophilic side chain on the piperazine nitrogen were designed to interact with particular hydrophilic residues in the binding pocket. This leads to analogues with moderate inhibitory activity on phosphodiesterase-5, even for isomers in which chiral carbons are of the S configuration.
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