Synthesis and structure-activity relationships of beta- and alpha-piperidine sulfone hydroxamic acid matrix metalloproteinase inhibitors with oral antitumor efficacy.

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Becker DP, Villamil CI, Barta TE, Bedell LJ, Boehm TL, Decrescenzo GA, Freskos JN, Getman DP, Hockerman S, Heintz R, Howard SC, Li MH, McDonald JJ, Carron CP, Funckes-Shippy CL, Mehta PP, Munie GE, Swearingen CA

Synthesis and structure-activity relationships of beta- and alpha-piperidine sulfone hydroxamic acid matrix metalloproteinase inhibitors with oral antitumor efficacy.

J Med Chem. 2005 Oct 20;48(21):6713-30.

PubMed ID
16220987 [ View in PubMed
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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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
CTS-1027Collagenase 3Ki (nM)0.67.525Details