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
  • 1. Cancer Research Area, Abbott Laboratories, Department 47J, Building AP10, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, USA. [email protected]
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.