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1Synthesis and Structure-Activity Relationships of Beta- and Alpha-Piperidine Sulfone Hydroxamic Acid Matrix Metalloproteinase Inhibitors with Oral Antitumor Efficacy.

Daniel P Becker,Clara I Villamil,Thomas E Barta,Louis J Bedell,Terri L Boehm,Gary A Decrescenzo,John N Freskos,Daniel P Getman,Susan Hockerman, Robert Heintz,Susan Carol Howard,Madeleine H Li,

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.

2005Journal of medicinal chemistry（2005）引用：71

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2Design and Synthesis of Potent and Selective 4,4-Substituted Alpha-Sulphones Hydroxamates As Mmp Inhibitors.