Specific inhibitors of cytochrome P450 26 retinoic acid hydroxylase

Inventors

Diaz, Philippe • Isoherranen, Nina • BUTTRICK, Brian • GUILLOTEAU, Nicolas

Assignees

University of Montana Missoula • University of Washington Center for Commercialization

Abstract

The present disclosure is generally directed to compositions and methods for treating diseases that are ameliorated by the inhibition of CYP26 mediated retinoic acid metabolism. The compositions comprise compounds of formula (I). A repreid50000060307390 IB/345 nullsents aryl optionally substituted with one, two, three, or four groups that are each independently halogen, cyano, nitro, C1-6 alkyl, C1-6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy; X is a bond, —CH2—, —CHR5—, —C═CHR4—, —NR4—, —N═O—R4—, —O—, —S—, —SO—, —SO2—, —C(O)—, or —C(NR4)—, or X is of formula (a), (b) or (c), wherein each n is independently 1, 2, or 3; each R4 is independently hydrogen or C1-6 alkyl; R5 is independently hydrogen, C1-6 alkyl, or —OR6, where R6 is selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyL C3-12 cycloalkyl, heterocyclyl, aryl, arylC1-6 alkyl, heteroaryl, or heteroarylC1-6 alkyl; Y is C1-6 alkylene, C2-6 alkenylene, or C2-6 alkylylene moiety.

Core Innovation

The invention is directed to novel compositions and methods for treating diseases that are ameliorated by inhibiting CYP26-mediated retinoic acid metabolism. Specifically, the invention claims compounds of formula (I), which are structurally defined by a scaffold that includes an aryl group, a variable linker (X), a spacer (Y), and defined substituents (R1, R2, R3), all with specific chemical options as disclosed. The invention also covers pharmaceutically acceptable salts and pharmaceutical compositions containing these compounds.

The underlying problem addressed by the invention is the limitation of therapeutic uses of retinoic acid (RA) isomers in cancer and dermatology due to side effects and resistance, which primarily occur as a result of increased RA metabolism by the cytochrome P450 CYP26 enzymes. The emergence of treatment resistance and side effects, such as teratogenicity and autoinduction of RA metabolism, hinders effective therapy. Prior approaches involving RA metabolism blocking agents (RAMBAs) have lacked selectivity or clinical approval.

By providing new inhibitors of CYP26, particularly targeting the predominant all-trans-retinoic acid hydroxylases CYP26A1 and CYP26B1, the invention proposes that endogenous RA concentrations can be increased in a cell-type specific manner. This potentiates the beneficial effect of endogenous RA while reducing side effects compared to direct RA administration and allows for more targeted, effective therapy for conditions such as certain cancers, neurodegenerative diseases, and dermatological conditions. Furthermore, these inhibitors are disclosed as being effective, and, in some cases, selective for CYP26A1 over CYP26B1, offering potential for differential modulation of RA metabolism.

Claims Coverage

The independent claims of the patent introduce the main inventive features related to specific chemical entities of formula (I), their functional group variations, and pharmaceutical compositions containing them.

In summary, the claims cover the described compounds of formula (I) featuring defined combinations of functional groups and substitutions, as well as pharmaceutical compositions containing such compounds formulated with acceptable carriers or excipients.

Stated Advantages

Documented Applications