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
Department of Biomedical and Pharmaceutical Sciences, The University of Montana , 32 Campus Drive, Missoula, Montana 59812, United States.
DermaXon LLC , 32 Campus Drive, Missoula, Montana 59812, United States.
J Med Chem. 2016 Mar 24;59(6):2579-95. doi: 10.1021/acs.jmedchem.5b01780. Epub 2016 Mar 15.
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.
细胞色素P450 CYP26酶负责全反式维甲酸（atRA）的清除。抑制CYP26酶会增加内源性atRA浓度，是一个有吸引力的治疗靶点。然而，现有的atRA代谢抑制剂对CYP26A1和CYP26B1的选择性和效力尚不清楚，且尚未开发出选择性CYP26A1或CYP26B1抑制剂。本文报道了首个CYP26A1选择性抑制剂的合成及其强效抑制活性。鉴定出了一系列低纳摩尔效力的非唑类CYP26A1选择性抑制剂。先导化合物3-{4-[2-(5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基)-1,3-二氧戊环-2-基]苯基}丙酸（24）对CYP26A1的选择性为43倍，IC50为340 nM。化合物24及其两个结构类似物也抑制HepG2细胞中的atRA代谢，导致atRA对RAR激活的效力增加。所鉴定的化合物有潜力成为旨在提高内源性atRA浓度的新型治疗方法，并且可能作为与atRA的联合治疗来对抗治疗耐药性。
