RESUMEN
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.
Asunto(s)
Antiinflamatorios/síntesis química , Antineoplásicos/síntesis química , Fármacos Cardiovasculares/síntesis química , Ácidos Hidroxámicos/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz , Piperidinas/síntesis química , Piranos/síntesis química , Sulfonas/síntesis química , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Disponibilidad Biológica , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/farmacología , Cartílago Articular/efectos de los fármacos , Cartílago Articular/patología , Bovinos , Cristalografía por Rayos X , Humanos , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Macaca fascicularis , Ratones , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Piperidinas/química , Piperidinas/farmacología , Piranos/química , Piranos/farmacología , Ratas , Relación Estructura-Actividad , Sulfonas/química , Sulfonas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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.