Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 57, Issue -, Pages 329-343Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2012.09.029
Keywords
PDE5 inhibitors; Tadalafil; Carbolines; Ensemble docking
Categories
Funding
- NCI NIH HHS [R01 CA131378, R01 CA148817, R01 CA155638] Funding Source: Medline
Ask authors/readers for more resources
By studying the co-crystal information of interactions between PDE5 and its inhibitors, forty new tetrahydro-beta-carbolines based-analogues were synthesized, and tested for their PDE5 inhibition. Some compounds were as active as tadalafil in inhibiting PDE5 and of better selectivity profile particularly versus PDE11A, the nature of the terminal ring and its nitrogen substituent are the main determinants of selectivity. Ensemble docking confirmed the role of H-loop closed conformer in activity versus its occluded and open forms. Conformational studies showed the effect of bulkiness of the terminal ring N-alkyl substituent on the formation of stable enzyme ligands conformers. The difference in potencies of hydantoin and piperazinedione analogues, together with the necessity of C-5/C-6 R-absolute configuration has been revealed through molecular docking. (C) 2012 Elsevier Masson SAS. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available