2. Academic Validation
  3. Phenoxyphenyl sulfone N-formylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors

Phenoxyphenyl sulfone N-formylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors

  • J Med Chem. 2002 Jan 3;45(1):219-32. doi: 10.1021/jm0103920.
Carol K Wada 1,  James H Holms,  Michael L Curtin,  Yujia Dai,  Alan S Florjancic,  Robert B Garland,  Yan Guo,  H Robin Heyman,  Jamie R Stacey,  Douglas H Steinman,  Daniel H Albert,  Jennifer J Bouska,  Ildiko N Elmore,  Carole L Goodfellow,  Patrick A Marcotte,  Paul Tapang,  Douglas W Morgan,  Michael R Michaelides,  Steven K Davidsen
Affiliations

Affiliation

  • 1 Cancer Research Area, Abbott Laboratories, Department 47J, Building AP10, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, USA. carol.wada@abbott.com
PMID: 11754593 DOI: 10.1021/jm0103920
Abstract

A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as Matrix Metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP Inhibitor that has been shown to significantly inhibit tumor growth in animal Cancer models.

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