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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2002年 / 45卷 / 01期

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

页码：219 / 232

页数：14

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