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

Charlotte M. N. Allerton,*‡ Christopher G. Barber,‡ Kevin C. Beaumont,§ David G. Brown, Susan M. Cole,§ David Ellis,‡ Charlotte A. L. Lane,‡ Graham N. Maw,‡ Natalie M. Mount, David J. Rawson,‡ Colin M. Robinson, Stephen D. A. Street,‡ and Nicholas W. Summerhill‡
Discovery Chemistry, Pharmacokinetics, Dynamics and Metabolism, Lead Discovery, and Discovery Biology, Pfizer Global Research & Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom
J. Med. Chem., 2006, 49 (12), pp 3581–3594
DOI: 10.1021/jm060113e
Publication Date (Web): May 24, 2006
Copyright © 2006 American Chemical Society
†

 Coordinates have been deposited for the structure of the complex of compound 2 with the catalytic domain of PDE5. PDB ID:  2CHM.

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*

 To whom correspondence should be addressed. Telephone:  +44 1304 616161. Fax:  +44 1304 651817. E-mail:  charlotte.allerton@pfizer.com.

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‡

 Discovery Chemistry.

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§

 Pharmacokinetics, Dynamics and Metabolism.

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 Lead Discovery.

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 Discovery Biology.

Abstract

Abstract Image

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 Cmax 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.

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  • Published In Issue June 15, 2006
  • Received February 2, 2006

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