| 17688073 |
Schneider F, Mattern-Dogru E, Hillgenberg M, Alken RG: Changed phosphodiesterase selectivity and enhanced in vitro efficacy by selective deuteration of sildenafil. Arzneimittelforschung. 2007;57(6):293-8.
In order to explore whether selective deuteration of sildenafil affects selectivity and efficacy of the drug, the inhibitory activity of sildenafil (1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d] pyri midin-5-yl) phenyl-sulfonyl] -4-methylpiperazine citrate, CAS 139755-83-2) and three deuterated sildenafil derivatives, D8-piperazine-sildenafil (BDD-10402), D3-methyl-D8-piperazine-sildenafil (BDD-10403) and D5-ethoxy-Sildenafil (BDD-10406) against phosphodiesterases 1-6 was compared. Furthermore, the relaxant effect of sildenafil and its deuterated derivatives in a contractility assay on rabbit corpus cavernosum strips from New Zealand rabbits was investigated. BDD-10406 exhibits a 2-fold higher selectivity for phosphodiesterase 5 versus phosphodiesterase 6 than sildenafil. BDD-10406 and sildenafil inhibited cGMP formation with IC50 values of 6 nmol/L and 9 nmol/L, respectively. The corresponding IC80 values for BDD-10406 and Sildenafil were 33 nmol/L and 40 nmol/L, respectively. Sildenafil, BDD-10402, BDD-10403 and BDD-10406 relaxed the rabbit corpus cavernosum strips in a dose-dependent manner with ED50 values of 245 nmol/L, 91 nmol/L, 121 nmol/L and 85 nmol/L, respectively. Deuteration of sildenafil on the ethoxy group (BDD-10406) leads to enhanced selectivity for phosphodiesterase 5 versus phosphodiesterase 6 and higher efficacy in vitro. This is the first example of a deuteration effect on the inhibitory activity of a reversible enzyme inhibitor. |
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