A Novel Series of Potent and Selective PDE5 Inhibitors with Potential for High and Dose-Independent Oral Bioavailability

Sildenafil (5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one), a potent and selective phosphodiesterase type 5 (PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-06, Vol.49 (12), p.3581-3594
Main Authors: Allerton, Charlotte M. N, Barber, Christopher G, Beaumont, Kevin C, Brown, David G, Cole, Susan M, Ellis, David, Lane, Charlotte A. L, Maw, Graham N, Mount, Natalie M, Rawson, David J, Robinson, Colin M, Street, Stephen D. A, Summerhill, Nicholas W
Format: Article
Language:English
Subjects:
3',5'-Cyclic-GMP Phosphodiesterases - antagonists & inhibitors
3',5'-Cyclic-GMP Phosphodiesterases - chemistry
Administration, Oral
Animals
Azetidines - chemical synthesis
Azetidines - chemistry
Azetidines - pharmacology
Biological and medical sciences
Biological Availability
Caco-2 Cells
Crystallography, X-Ray
Cyclic Nucleotide Phosphodiesterases, Type 5
Dogs
Dose-Response Relationship, Drug
Erectile Dysfunction - drug therapy
Humans
Ketones - chemistry
Male
Medical sciences
Miscellaneous
Models, Molecular
Molecular Structure
Pharmacology. Drug treatments
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Pyrimidines - pharmacology
Pyrimidinones - chemical synthesis
Pyrimidinones - chemistry
Pyrimidinones - pharmacology
Structure-Activity Relationship
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Summary:Sildenafil (5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one), a potent and selective phosphodiesterase type 5 (PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported in this paper was to combine high levels of PDE5 potency and selectivity with high and dose-independent oral bioavailability, to minimize the impact on the C max of any interactions with coadministered drugs in the clinic. This goal was achieved through identification of a lower clearance series with a high absorption profile, by replacing the 5‘-piperazine sulfonamide in the sildenafil template with a 5‘-methyl ketone. This novel series provided compounds with low metabolism in human hepatocytes, excellent caco-2 flux, and the potential for good aqueous solubility. The in vivo oral and iv pharmacokinetic profiles of example compounds confirmed the high oral bioavailability predicted from these in vitro screens. 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2) was selected for progression into the clinic.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm060113e