Carol K Wada, 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
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.
