Orally active MMP-1 sparing α-tetrahydropyranyl and α-piperidinyl sulfone matrix metalloproteinase (MMP) inhibitors with efficacy in cancer, arthritis, and cardiovascular disease

  • J Med Chem. 2010 Sep 23;53(18):6653-80. doi: 10.1021/jm100669j.
Daniel P Becker  1 ,  Thomas E Barta ,  Louis J Bedell ,  Terri L Boehm ,  Brian R Bond ,  Jeffery Carroll ,  Chris P Carron ,  Gary A Decrescenzo ,  Alan M Easton ,  John N Freskos ,  Chris L Funckes-Shippy ,  Marcia Heron ,  Susan Hockerman ,  Carol Pearcy Howard ,  James R Kiefer ,  Madeleine H Li ,  Karl J Mathis ,  Joseph J McDonald ,  Pramod P Mehta ,  Grace E Munie ,  Teresa Sunyer ,  Craig A Swearingen ,  Clara I Villamil ,  Dean Welsch ,  Jennifer M Williams ,  Ying Yu ,  Jun Yao
Affiliations
  • 1. Pfizer Research, 700 Chesterfield Village Parkway, St. Louis, Missouri 63198, USA. [email protected]
PMID: 20726512 DOI: 10.1021/jm100669j
Abstract

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.

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