Abstract
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.
MeSH terms
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Administration, Oral
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Angiogenesis Inhibitors / chemical synthesis
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Angiogenesis Inhibitors / chemistry
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Angiogenesis Inhibitors / pharmacology
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Female
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Hydroxamic Acids / chemical synthesis*
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Hydroxamic Acids / chemistry
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Hydroxamic Acids / pharmacology
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Mammary Neoplasms, Experimental / drug therapy
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Mammary Neoplasms, Experimental / mortality
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Matrix Metalloproteinase Inhibitors*
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Mice
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Mice, Nude
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Paclitaxel / therapeutic use
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / pharmacology
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Structure-Activity Relationship
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Sulfones / chemical synthesis*
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Sulfones / chemistry
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Sulfones / pharmacology
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Xenograft Model Antitumor Assays
Substances
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Angiogenesis Inhibitors
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Antineoplastic Agents
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Hydroxamic Acids
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Matrix Metalloproteinase Inhibitors
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N-hydroxy-4-((4-(phenylthio)phenyl)sulfonyl)-1-(2-propynyl)-4-piperidinecarboxamide
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Piperidines
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Sulfones
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Paclitaxel