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

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Wada CK, Holms JH, Curtin ML, Dai Y, Florjancic AS, Garland RB, Guo Y, Heyman HR, Stacey JR, Steinman DH, Albert DH, Bouska JJ, Elmore IN, Goodfellow CL, Marcotte PA, Tapang P, Morgan DW, Michaelides MR, Davidsen SK

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

J Med Chem. 2002 Jan 3;45(1):219-32.

PubMed ID
11754593 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
Marimastat72 kDa type IV collagenaseIC 50 (nM)0.41N/AN/ADetails
MarimastatCollagenase 3IC 50 (nM)1.2N/AN/ADetails
MarimastatInterstitial collagenaseIC 50 (nM)0.78N/AN/ADetails
MarimastatMatrilysinIC 50 (nM)4.1N/AN/ADetails
MarimastatNeutrophil collagenaseIC 50 (nM)0.47N/AN/ADetails
MarimastatStromelysin-1IC 50 (nM)14N/AN/ADetails