ABSTRACT
Continuing our interest in designing compounds preferentially potent and selective for MMP-13, we report on a series of hydroxamic acids with a flexible amide P1' substituents. We identify an amide which spares both MMP-1 and -14, and shows >500 fold selectivity for MMP-13 versus MMP-2 and -8.
Subject(s)
Amides/chemical synthesis , Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemical synthesis , Amides/chemistry , Humans , Hydroxamic Acids/chemistry , Inhibitory Concentration 50 , Molecular Structure , Protease Inhibitors/chemistry , Structure-Activity Relationship , Substrate SpecificityABSTRACT
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.
Subject(s)
Amides/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Sulfones/chemical synthesis , Amides/chemistry , Animals , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Heterocyclic Compounds/chemistry , Hydroxamic Acids/chemistry , Matrix Metalloproteinase 13/chemistry , Models, Molecular , Rats , Structure-Activity Relationship , Substrate Specificity , Sulfones/chemistryABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , Cardiovascular Agents/chemical synthesis , Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Piperidines/chemical synthesis , Pyrans/chemical synthesis , Sulfones/chemical synthesis , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biological Availability , Cardiovascular Agents/chemistry , Cardiovascular Agents/pharmacology , Cartilage, Articular/drug effects , Cartilage, Articular/pathology , Cattle , Crystallography, X-Ray , Humans , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Hypertrophy, Left Ventricular/drug therapy , Macaca fascicularis , Mice , Mice, Nude , Models, Molecular , Molecular Structure , Piperidines/chemistry , Piperidines/pharmacology , Pyrans/chemistry , Pyrans/pharmacology , Rats , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
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.
