Modulation of Cytochrome-P450 Inhibition (CYP) in Drug Discovery: A Medicinal Chemistry Perspective

Abstract

Cytochrome P450 (CYP450) has widely been implicated for drug-drug interactions (DDI) in the pharmaceutical industry. Inhibition or induction of this enzyme family has led to withdrawal of multiple drugs from the market leading to major time and financial losses for the pharmaceutical industry. CYP450 plays a prevailing role in the biotransformation of a large number of structurally diverse drugs. Few isoenzymes of the CYP enzyme family (CYP3A4, 2D6 and 2C9 family) are mainly involved in metabolism of most of the drugs. To avoid such interactions and potentially minimize DDI, major pharmaceutical organizations prefer to incorporate CYP enzyme screening at an early stage of their discovery program. While this has been a prevalent practice in the pharmaceutical industry lately, there is very limited literature available reviewing the relationship between chemotypes and CYP isoforms. This review will collate literature pertaining to CYP-inhibition modulation through physicochemical parameters and chemical modification and thus bring to focus commonly used trends by medicinal chemists world-wide.

Discovery of a Potent BTK Inhibitor with a Novel Binding Mode by Using Parallel Selections with a DNA‐Encoded Chemical Library

“…Compound 3 was also tested for cytochrome P450 (Cyp) inhibition. Cyp enzymes such as Cyp3A4, Cyp2C9, and Cyp2D6 are largely responsible for drug metabolism in the liver, and lack of Cyp inhibition greatly reduces the likelihood of drug–drug interactions that could lead to potential adverse events in patients by inhibiting metabolism of other drugs . Compound 3 showed no inhibition of these three major cytochromes, further strengthening the case that this molecule, identified directly from an on‐DNA library, is a good starting point for a clinical candidate.…”

Primaquine pharmacology in the context of CYP 2D6 pharmacogenomics: Current state of the art

“…CYP 2D6 is a cytochrome P450 hepatic enzyme that is responsible for the metabolism of 20-25 % of clinically used drugs (Kumar, Sharma, & Roychowdhury, 2012;Preissner, et al, 2013;Zanger, Raimundo, & Eichelbaum, 2004;Zanger & Schwab, 2013). This structural promiscuity is an important aspect of CYP 2D6 mediated metabolism because despite the large number of CYP 2D6 substrates, CYP 2D6 only constitutes a small percentage of total hepatic…”

Herbal Bioenhancers in Veterinary Phytomedicine

“…Inhibition will lead fewer drug molecules to be metabolyzed with an increased concentration of untransformed drug passing from gut into the blood. Major isoenzymes among CYPs, involved in the metabolism of drugs in humans are CYP3A4, 2D6 and 2C9 family ( 9 ). Eventhough orthologue families are present in different animal species with structural similarities and substrate ranges comparable to humans; the species specific differences should be well considered for bioenhancing through enzymatic alterations.…”