When Cofactors Aren't X Factors: Functional Groups That Are Labile in Human Liver Microsomes in the Absence of NADPH

Matthew L Landry; Richard Trager; Fabio Broccatelli; James J Crawford

doi:10.1021/acsmedchemlett.2c00071

When Cofactors Aren't X Factors: Functional Groups That Are Labile in Human Liver Microsomes in the Absence of NADPH

ACS Med Chem Lett. 2022 Mar 11;13(4):727-733. doi: 10.1021/acsmedchemlett.2c00071. eCollection 2022 Apr 14.

Authors

Matthew L Landry¹, Richard Trager¹, Fabio Broccatelli¹, James J Crawford¹

Affiliation

¹ Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.

Abstract

The metabolic stability of compounds is often assessed at an early stage in drug discovery programs by profiling with hepatic microsomes. Exclusion of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) in these assays provides insight into non-cytochrome P450 (CYP)-mediated metabolism. This report uses a matched molecular pair (MMP) application to assess which chemical substituents are commonly susceptible to non-NADPH-mediated metabolism by microsomes. The analysis found the overall prevalence of metabolism in the absence of NADPH to be low, with esters, amides, aldehydes, and oxetanes being among the most commonly susceptible functional groups. Given that non-CYP enzymes, such as esterases, may be expressed extrahepatically and lead to lower confidence in predicted pharmacokinetic profiles, an awareness of the functional groups that commonly undergo non-NADPH-mediated metabolism-as well as options for their replacement based on experimental MMP data-may help researchers derisk metabolic stability issues at an earlier stage in drug discovery.