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

被引:101
作者
Wada, CK [1 ]
Holms, JH [1 ]
Curtin, ML [1 ]
Dai, Y [1 ]
Florjancic, AS [1 ]
Garland, RB [1 ]
Guo, Y [1 ]
Heyman, HR [1 ]
Stacey, JR [1 ]
Steinman, DH [1 ]
Albert, DH [1 ]
Bouska, JJ [1 ]
Elmore, IN [1 ]
Goodfellow, CL [1 ]
Marcotte, PA [1 ]
Tapang, P [1 ]
Morgan, DW [1 ]
Michaelides, MR [1 ]
Davidsen, SK [1 ]
机构
[1] Abbott Labs, Canc Res Area, Dept 47J, Abbott Pk, IL 60064 USA
关键词
D O I
10.1021/jm0103920
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:219 / 232
页数:14
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