Synthesis and Structure−Activity Relationships of β- and α-Piperidine Sulfone Hydroxamic Acid Matrix Metalloproteinase Inhibitors with Oral Antitumor Efficacy

α-Piperidine-β-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 β-sulfones subsequently led to the discovery of hitherto unknown α-sulfone hydroxamates that are superior to the correspo...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2005-10, Vol.48 (21), p.6713-6730
Main Authors: Becker, Daniel P, Villamil, Clara I, Barta, Thomas E, Bedell, Louis J, Boehm, Terri L, DeCrescenzo, Gary A, Freskos, John N, Getman, Daniel P, Hockerman, Susan, Heintz, Robert, Howard, Susan Carol, Li, Madeleine H, McDonald, Joseph J, Carron, Chris P, Funckes-Shippy, Chris L, Mehta, Pramod P, Munie, Grace E, Swearingen, Craig A
Format: Article
Language:English
Subjects:
Administration, Oral
Angiogenesis Inhibitors - chemical synthesis
Angiogenesis Inhibitors - chemistry
Angiogenesis Inhibitors - pharmacology
Animals
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Biological and medical sciences
Female
General aspects
Hydroxamic Acids - chemical synthesis
Hydroxamic Acids - chemistry
Hydroxamic Acids - pharmacology
Mammary Neoplasms, Experimental - drug therapy
Mammary Neoplasms, Experimental - mortality
Matrix Metalloproteinase Inhibitors
Medical sciences
Mice
Mice, Nude
Paclitaxel - therapeutic use
Pharmacology. Drug treatments
Piperidines - chemical synthesis
Piperidines - chemistry
Piperidines - pharmacology
Structure-Activity Relationship
Sulfones - chemical synthesis
Sulfones - chemistry
Sulfones - pharmacology
Xenograft Model Antitumor Assays
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Summary:α-Piperidine-β-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 β-sulfones subsequently led to the discovery of hitherto unknown α-sulfone hydroxamates that are superior to the corresponding β-sulfones in potency for target MMPs, selectivity vs MMP-1, and exposure when dosed orally. α-Piperidine-α-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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0500875