RESUMEN
BACKGROUND: First- and third-generation retinoids are the main treatment for acne. Even though efficacious, they lack full selectivity for retinoic acid receptor (RAR) γ, expressed in the epidermis and infundibulum. OBJECTIVES: To characterize the in vitro metabolism and the pharmacology of the novel retinoid trifarotene. MATERIALS AND METHODS: In vitro assays determined efficacy, potency and selectivity on RARs, as well as the activity on the expression of retinoid target genes in human keratinocytes and ex vivo cultured skin. In vivo studies investigated topical comedolytic, anti-inflammatory and depigmenting properties. The trifarotene-induced gene expression profile was investigated in nonlesional skin of patients with acne and compared with ex vivo and in vivo models. Finally, the metabolic stability in human keratinocytes and hepatic microsomes was established. RESULTS: Trifarotene is a selective RARγ agonist with > 20-fold selectivity over RARα and RARß. Trifarotene is active and stable in keratinocytes but rapidly metabolized by human hepatic microsomes, predicting improved safety. In vivo, trifarotene 0·01% applied topically is highly comedolytic and has anti-inflammatory and antipigmenting properties. Gene expression studies indicated potent activation of known retinoid-modulated processes (epidermal differentiation, proliferation, stress response, retinoic acid metabolism) and novel pathways (proteolysis, transport/skin hydration, cell adhesion) in ex vivo and in vivo models, as well as in human skin after 4 weeks of topical application of trifarotene 0·005% cream. CONCLUSIONS: Based on its RARγ selectivity, rapid degradation in human hepatic microsomes and pharmacological properties including potent modulation of epidermal processes, topical treatment with trifarotene could result in good efficacy and may present a favourable safety profile in acne and ichthyotic disorders.
Asunto(s)
Acné Vulgar/tratamiento farmacológico , Fármacos Dermatológicos/farmacología , Receptores de Ácido Retinoico/agonistas , Retinoides/farmacología , Acné Vulgar/patología , Administración Cutánea , Animales , Biopsia , Diferenciación Celular/efectos de los fármacos , Línea Celular , Fármacos Dermatológicos/uso terapéutico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Estabilidad de Medicamentos , Expresión Génica/efectos de los fármacos , Perfilación de la Expresión Génica , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Ratones , Microsomas Hepáticos , Retinoides/uso terapéutico , Piel , Pigmentación de la Piel/efectos de los fármacos , Técnicas de Cultivo de Tejidos , Receptor de Ácido Retinoico gammaRESUMEN
From a series of naphthalene and benzoic acid derivatives we have identified synthetic retinoic acid analogues exhibiting high selectivity for the nuclear retinoic acid receptors RAR alpha (Am 580), RAR beta (CD 2019) and RAR gamma (CD 437) as well as ligands sharing high affinities for all RAR subtypes (CD 367). The compounds were evaluated in two complementary screening systems: (1) binding to nuclear proteins extracted from COS-7 cells after transfection with the appropriate expression vectors, and (2) induction of plasminogen activator in the embryonic mouse teratocarcinoma cell line F9. All compounds behaved as retinoic acid agonists in the F9 test.