Medicinal chemistry strategies to reduce CYP2D6 inhibitory activity of lead candidates.
Among the various human cytochrome P450s (CYP450s) that catalyze the biotransformation of xenobiotics, CYP450 2D6 (CYP2D6) is one of the most important based on the number and wide variety of its drug substrates. CYP2D6 shows a high degree of interindividual variability, which is primarily due to the extensive genetic polymorphism that influences its expression and function. A number of drugs have been clinically implicated in major drug-drug interactions (DDI) via CYP2D6 inhibition. In order to avoid or minimize issues related to CYP2D6-mediated DDIs, pharmaceutical companies routinely screen for potential CYP2D6 liability of lead candidates in the early stage of the drug discovery process. This review summarizes the medicinal chemistry tactics employed to mitigate inhibitory activity at CYP2D6, identified through an extensive literature survey covering the 1998-2008 period.
Le Bourdonnec
Bertrand
B
Department of Chemistry, Adolor Corporation, Exton, PA 19341, USA. blebourdonnec@adolor.com
Leister
Lara K
LK
D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000494:pharmacology; D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology; D000889:Anti-Arrhythmia Agents / Q000737:chemistry / Q000494:pharmacology; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D015195:Drug Design; D006801:Humans; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D000700:Analgesics; D000889:Anti-Arrhythmia Agents; D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D020033:Protein Isoforms; D019389:Cytochrome P-450 CYP2D6