Late-Stage Microsomal Oxidation Reduces Drug-Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189

  • ACS Med Chem Lett. 2018 Jan 4;9(2):68-72. doi: 10.1021/acsmedchemlett.7b00343.
Antonia F Stepan  1 ,  Tuan P Tran  2 ,  Christopher J Helal  2 ,  Maria S Brown  2 ,  Cheng Chang  2 ,  Rebecca E O'Connor  2 ,  Michael De Vivo  1 ,  Shawn D Doran  2 ,  Ethan L Fisher  2 ,  Stephen Jenkinson  3 ,  David Karanian  2 ,  Bethany L Kormos  1 ,  Raman Sharma  2 ,  Gregory S Walker  2 ,  Ann S Wright  2 ,  Edward X Yang  2 ,  Michael A Brodney  1 ,  Travis T Wager  1 ,  Patrick R Verhoest  1 ,  R Scott Obach  2
Affiliations
  • 1. Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, Massachusetts 02139, United States.
  • 2. Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States.
  • 3. Pfizer Worldwide Research and Development, 10770 Science Center Drive, La Jolla, California 92121, United States.
PMID: 29456790 DOI: 10.1021/acsmedchemlett.7b00343
Abstract

Late-stage oxidation using liver microsomes was applied to phosphodiesterase 2 inhibitor 1 to reduce its clearance by Cytochrome P450 enzymes, introduce renal clearance, and minimize the risk for victim drug-drug interactions. This approach yielded PF-06815189 (2) with improved physicochemical properties and a mixed metabolic profile. This example highlights the importance of C-H diversification methods to drug discovery.

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