Project Grant R43AR083781

SELECTIVE CYP26 INHIBITORS FOR THE ORAL TREATMENT OF RECALCITRANT NODULAR ACNE. - PROJECT SUMMARY / ABSTRACT DERMAXON'S PROJECT GOAL IS TO DEVELOP EFFICACIOUS, SUBSTRATE-BASED, SELECTIVE INHIBITORS OF CYP26S, THE ENZYMES RESPONSIBLE FOR THE METABOLISM OF ALL-TRANS RETINOIC ACID (ATRA) IN THE EPIDERMIS, AS AN ORAL TREATMENT FOR SEVERE RECALCITRANT ACNE. THIS APPROACH WILL PROVIDE AN IMPROVED ACNE THERAPEUTIC WITHOUT THE ADVERSE EFFECTS ASSOCIATED WITH CURRENTLY MARKETED RETINOIDS. THIS WOULD ALSO AVOID THE POTENTIAL ADVERSE EFFECTS CAUSED BY THE OFF-TARGET CYTOCHROME P450 (CYP) INHIBITION SEEN WITH PREVIOUSLY INVESTIGATED AZOLE-CONTAINING CYP26 INHIBITORS SUCH AS LIAROZOLE. ACNE AFFECTS MORE THAN 40 MILLION AMERICANS, COSTS UPWARDS OF $3 BILLION ANNUALLY, AND HAS A SIGNIFICANT NEGATIVE IMPACT ON QUALITY OF LIFE. ACNE PATIENTS HAVE BEEN SHOWN TO EXPERIENCE LEVELS OF SOCIAL, PSYCHOLOGICAL AND EMOTIONAL DISTRESS SIMILAR TO THOSE REPORTED IN EPILEPTIC AND DIABETIC PATIENTS. RETINOIDS, A CLASS OF ATRA-RELATED COMPOUNDS, POSSESS COMEDOLYTIC AND ANTI-INFLAMMATORY PROPERTIES. HOWEVER, CONSIDERABLE ADVERSE EFFECTS INCLUDING ERYTHEMA, PRURITUS, DRYNESS, AND PEELING, AS WELL AS SYSTEMIC ADVERSE EFFECTS ON MUCOCUTANEOUS, MUSCULOSKELETAL, AND OPHTHALMIC SYSTEMS, ARE LIMITING FACTORS. CLEARANCE OF ATRA IN THE SKIN IS PREDOMINANTLY MEDIATED BY THE CYP FAMILY 26 ISOFORMS CYP26A1 AND CYP26B1. CURRENTLY APPROVED TOPICAL RETINOIDS TARGETING DIRECT ACTIVATION OF RETINOIC ACID RECEPTORS, ARE ALSO POTENT INHIBITORS OF BOTH CYP26A1 AND B1, WHICH LIKELY EXPLAINS THEIR ADVERSE SIDE EFFECTS RELATED TO RETINOID PATHWAY OVERSTIMULATION. WE HAVE POTENT AND SELECTIVE INHIBITORS OF CYP26A1 AND/OR B1. OUR PRELIMINARY DATA DEMONSTRATES THAT THESE INHIBITORS: A) ARE SPECIFIC CYP26 INHIBITOR WHICH DO NOT INTERACT WITH NUCLEAR RECEPTORS AND OFF-TARGET CYPS, B) POTENTIATES THE EFFECTS OF A NANOMOLAR CONCENTRATION OF ATRA IN RECONSTRUCTED HUMAN EPIDERMIS, C) ARE NOT GENOTOXIC, CARDIOTOXIC, OR IRRITANT, D) EXHIBITS COMEDOLYTIC EFFICACY IN VIVO E) ARE ORALLY BIOAVAILABLE AND F) ARE MANUFACTURABLE. THE STUDIES IN AIM 1 FOCUS ON COMPLETING THE ORAL CHARACTERIZATION OF THESE COMPOUNDS AND THEIR BIODISTRIBUTION IN SKIN AND PLASMA IN VIVO. THE STUDIES IN AIM 2 WILL FOCUS ON THE ORAL DOSE RANGE EFFICACY STUDIES IN RHINO MICE. IN AIM 3, WE WILL DETERMINE THE EMBRYO-FETAL DEVELOPMENT TOXICITY OF THE SELECTED INHIBITOR AT THE ACTIVE DOSE. BY THE END OF THIS PROJECT, DERMAXON WILL HAVE IDENTIFIED AN ORAL CYP26 READY FOR IND-ENABLING STUDIES ADDRESSING THE THERAPEUTIC NEEDS OF SEVERE ACNE PATIENTS.