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

Stepan, Antonia F.; Tran, Tuan P.; Helal, Christopher J.; Brown, Maria S.; Chang, Cheng; O’Connor, Rebecca E.; De Vivo, Michael; Doran, Shawn D.; Fisher, Ethan L.; Jenkinson, Stephen; Karanian, David; Kormos, Bethany L.; Sharma, Raman; Walker, Gregory S.; Wright, Ann S.; Yang, Edward X.; Brodney, Michael A.; Wager, Travis T.; Verhoest, Patrick R.; Obach, R. Scott

doi:10.1021/acsmedchemlett.7b00343.s001

ml7b00343_si_001.pdf (4.14 MB)

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

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posted on 2018-01-04, 00:00 authored by Antonia F. Stepan, Tuan P. Tran, Christopher J. Helal, Maria S. Brown, Cheng Chang, Rebecca E. O’Connor, Michael De Vivo, Shawn D. Doran, Ethan L. Fisher, Stephen Jenkinson, David Karanian, Bethany L. Kormos, Raman Sharma, Gregory S. Walker, Ann S. Wright, Edward X. Yang, Michael A. Brodney, Travis T. Wager, Patrick R. Verhoest, R. Scott Obach

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.

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

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