1. Late-Stage Microsomal Oxidation Reduces Drug-Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189
- Author
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Michael Aaron Brodney, Michael De Vivo, Ann S. Wright, Stephen Jenkinson, Shawn D. Doran, Patrick Robert Verhoest, Maria S. Brown, Gregory S. Walker, Christopher John Helal, Antonia F. Stepan, Travis T. Wager, R. Scott Obach, Ethan Lawrence Fisher, Tuan P. Tran, Bethany L. Kormos, Raman Sharma, Cheng Chang, Edward X. Yang, Rebecca E. O’Connor, and David Karanian
- Subjects
0301 basic medicine ,Pharmacology ,010402 general chemistry ,01 natural sciences ,Biochemistry ,03 medical and health sciences ,late-stage oxidation ,Drug Discovery ,drug−drug interactions ,Liver microsomes ,chemistry.chemical_classification ,biology ,Chemistry ,Drug discovery ,Organic Chemistry ,Phosphodiesterase ,Cytochrome P450 ,renal clearance ,Featured Letter ,0104 chemical sciences ,030104 developmental biology ,Enzyme ,Microsome ,biology.protein ,Phosphodiesterase 2 ,PDE2 ,liver microsomes ,Clearance - 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.
- Published
- 2017