Development and Characterization of Novel and Selective Inhibitors of Cytochrome P450 CYP26A1, the Human Liver Retinoic Acid Hydroxylase

Cytochrome P450 CYP26 enzymes are responsible for all-trans-retinoic acid (atRA) clearance. Inhibition of CYP26 enzymes will increase endogenous atRA concentrations and is an attractive therapeutic target. However, the selectivity and potency of the existing atRA metabolism inhibitors toward CYP26A1...

Full description

Saved in:

Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 59; no. 6; pp. 2579 - 2595
Main Authors:	Diaz, Philippe, Huang, Weize, Keyari, Charles M, Buttrick, Brian, Price, Lauren, Guilloteau, Nicolas, Tripathy, Sasmita, Sperandio, Vanessa G, Fronczek, Frank R, Astruc-Diaz, Fanny, Isoherranen, Nina
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 24-03-2016
Subjects:	Algorithms Animals Cell Line, Tumor Cytochrome P-450 Enzyme System - drug effects Drug Design Drug Resistance Enzyme Induction Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacology Humans Isoenzymes - antagonists & inhibitors Kinetics Liver - drug effects Liver - enzymology Rats Retinoic Acid 4-Hydroxylase Structure-Activity Relationship Substrate Specificity Tretinoin - metabolism
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Cytochrome P450 CYP26 enzymes are responsible for all-trans-retinoic acid (atRA) clearance. Inhibition of CYP26 enzymes will increase endogenous atRA concentrations and is an attractive therapeutic target. However, the selectivity and potency of the existing atRA metabolism inhibitors toward CYP26A1 and CYP26B1 is unknown, and no selective CYP26A1 or CYP26B1 inhibitors have been developed. Here the synthesis and potent inhibitory activity of the first CYP26A1 selective inhibitors is reported. A series of nonazole CYP26A1 selective inhibitors was identified with low nM potency. The lead compound 3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolan-2-yl] phenyl}4-propanoic acid (24) had 43-fold selectivity toward CYP26A1 with an IC50 of 340 nM. Compound 24 and its two structural analogues also inhibited atRA metabolism in HepG2 cells, resulting in increased potency of atRA toward RAR activation. The identified compounds have potential to become novel treatments aiming to elevate endogenous atRA concentrations and may be useful as cotreatment with atRA to combat therapy resistance.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/acs.jmedchem.5b01780