Orally Active MMP-1 Sparing α-Tetrahydropyranyl and α-Piperidinyl Sulfone Matrix Metalloproteinase (MMP) Inhibitors with Efficacy in Cancer, Arthritis, and Cardiovascular Disease

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2010-09, Vol.53 (18), p.6653-6680
Main Authors: Becker, Daniel P, Barta, Thomas E, Bedell, Louis J, Boehm, Terri L, Bond, Brian R, Carroll, Jeffery, Carron, Chris P, DeCrescenzo, Gary A, Easton, Alan M, Freskos, John N, Funckes-Shippy, Chris L, Heron, Marcia, Hockerman, Susan, Howard, Carol Pearcy, Kiefer, James R, Li, Madeleine H, Mathis, Karl J, McDonald, Joseph J, Mehta, Pramod P, Munie, Grace E, Sunyer, Teresa, Swearingen, Craig A, Villamil, Clara I, Welsch, Dean, Williams, Jennifer M, Yu, Ying, Yao, Jun
Format: Article
Language:English
Subjects:
Animals
Anti-Inflammatory Agents - chemical synthesis
Anti-Inflammatory Agents - chemistry
Anti-Inflammatory Agents - pharmacology
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological Availability
Cardiovascular Agents - chemical synthesis
Cardiovascular Agents - chemistry
Cardiovascular Agents - pharmacology
Cartilage, Articular - drug effects
Cartilage, Articular - pathology
Cattle
Crystallography, X-Ray
Humans
Hydroxamic Acids - chemical synthesis
Hydroxamic Acids - chemistry
Hydroxamic Acids - pharmacology
Hypertrophy, Left Ventricular - drug therapy
Macaca fascicularis
Matrix Metalloproteinase Inhibitors
Mice
Mice, Nude
Models, Molecular
Molecular Structure
Piperidines - chemical synthesis
Piperidines - chemistry
Piperidines - pharmacology
Pyrans - chemical synthesis
Pyrans - chemistry
Pyrans - pharmacology
Rats
Structure-Activity Relationship
Sulfones - chemical synthesis
Sulfones - chemistry
Sulfones - pharmacology
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm100669j