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 towards 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 non-azole 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 towards CYP26A1 with an IC50 of 340 nM. Compound 24 and its two structural analogs also inhibited atRA metabolism in HepG2 cells resulting in increased potency of atRA towards 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.

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Date of publication: 26 February 2016; Journal of Medicinal Chemistry

Author information: Philippe Diaz (2,4); Weize Huang (1); Charles M. Keyari (2); Brian Buttrick (1); Lauren Price (1); Nicholas Guilloteau (4); Sasmita Tripathy (1); Vanessa G. Sperandio (2); Frank R. Fronczek (3); Fanny Astruc-Diaz (4); & Nina Isoherranen (1)

(1) Department of Pharmaceutics, University of Washington, 1959 NE Pacific Street, Health Sciences Building, Box 357610, Seattle, Washington 98195, United States
(2) Department of Biomedical and Pharmaceutical Sciences, The University of Montana, 32 Campus Drive, Missoula, Montana 59812, United States
(3) Chemistry Department, Lousiana State Univeristy, 232 Choppin Hall, Baton Rouge, Louisiana 70803, United States
(4) DermaXon LLC, 32 Campus Drive, Missoula, Montana 59812, United States

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