Changed phosphodiesterase selectivity and enhanced in vitro efficacy by selective deuteration of sildenafil.
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]pyrimidin-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.
BiRDS Pharma GmbH, Berlin, Germany. fschneider@birdspharma.com
Frank
F
Schneider
Emine
E
Mattern-Dogru
Moritz
M
Hillgenberg
Rudolf-Giesbert
RG
Alken
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism; D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D003903:Deuterium / Q000737:chemistry; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D009599:Nitroprusside / Q000494:pharmacology; D010413:Penis / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011687:Purines / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D009599:Nitroprusside; D003903:Deuterium; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5