1. A Novel Series of Potent and Selective PDE5 Inhibitors with Potential for High and Dose-Independent Oral Bioavailability
- Author
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Barber Christopher Gordon, David James Rawson, Maw Graham Nigel, Natalie M. Mount, David G. Brown, Charlotte Moira Norfor Allerton, Susan M. Cole, Charlotte Alice Louise Lane, David Ellis, Nicholas W. Summerhill, Colin Robinson, Kevin Beaumont, and Street Stephen Derek Albert
- Subjects
Male ,Models, Molecular ,Sildenafil ,Cmax ,Administration, Oral ,Biological Availability ,Pyrimidinones ,Pharmacology ,Crystallography, X-Ray ,Structure-Activity Relationship ,chemistry.chemical_compound ,Dogs ,Erectile Dysfunction ,Pharmacokinetics ,3',5'-Cyclic-GMP Phosphodiesterases ,In vivo ,Oral administration ,Drug Discovery ,Animals ,Humans ,Cyclic Nucleotide Phosphodiesterases, Type 5 ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Ketones ,Bioavailability ,Pyrimidines ,chemistry ,Biochemistry ,Enzyme inhibitor ,cGMP-specific phosphodiesterase type 5 ,biology.protein ,Azetidines ,Molecular Medicine ,Caco-2 Cells - Abstract
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.
- Published
- 2006
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