RESUMEN
Seeking compounds preferentially potent and selective for MMP-13, we reported in the preceding Letter on a series of hydroxamic acids with a flexible benzamide tail groups.(1a) Here, we replace the amide moiety with non-hydrolyzable heterocycles in an effort to improve half-life. We identify a hydroxamate tetrazole 4e that spares MMP-1 and -14, shows >400-fold selectivity versus MMP-8 and >600-fold selectivity versus MMP-2, and has a 4.8 h half-life in rats. X-ray data (1.9 Å) for tetrazole 4c is presented.
Asunto(s)
Amidas/síntesis química , Inhibidores Enzimáticos/síntesis química , Compuestos Heterocíclicos/síntesis química , Ácidos Hidroxámicos/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz , Sulfonas/síntesis química , Amidas/química , Animales , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Compuestos Heterocíclicos/química , Ácidos Hidroxámicos/química , Metaloproteinasa 13 de la Matriz/química , Modelos Moleculares , Ratas , Relación Estructura-Actividad , Especificidad por Sustrato , Sulfonas/químicaRESUMEN
alpha-Piperidine-beta-sulfone hydroxamate derivatives were explored that are potent for matrix metalloproteinases (MMP)-2, -9, and -13 and are sparing of MMP-1. The investigation of the beta-sulfones subsequently led to the discovery of hitherto unknown alpha-sulfone hydroxamates that are superior to the corresponding beta-sulfones in potency for target MMPs, selectivity vs MMP-1, and exposure when dosed orally. alpha-Piperidine-alpha-sulfone hydroxamate 35f (SC-276) was advanced through antitumor and antiangiogenesis assays and was selected for development. Compound 35f demonstrates excellent antitumor activity vs MX-1 breast tumor in mice when dosed orally as monotherapy or in combination with paclitaxel.
Asunto(s)
Antineoplásicos/síntesis química , Ácidos Hidroxámicos/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz , Piperidinas/síntesis química , Sulfonas/síntesis química , Administración Oral , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/mortalidad , Ratones , Ratones Desnudos , Paclitaxel/uso terapéutico , Piperidinas/química , Piperidinas/farmacología , Relación Estructura-Actividad , Sulfonas/química , Sulfonas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
α-Sulfone-α-piperidine and α-tetrahydropyranyl hydroxamates were explored that are potent inhibitors of MMP's-2, -9, and -13 that spare MMP-1, with oral efficacy in inhibiting tumor growth in mice and left-ventricular hypertrophy in rats and in the bovine cartilage degradation ex vivo explant system. α-Piperidine 19v (SC-78080/SD-2590) was selected for development toward the initial indication of cancer, while α-piperidine and α-tetrahydropyranyl hydroxamates 19w (SC-77964) and 9i (SC-77774), respectively, were identified as backup compounds.