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
Drug Target Property Measurement pH Temperature (°C) Marimastat 72 kDa type IV collagenase IC 50 (nM) 0.41 N/A N/A Details Marimastat Collagenase 3 IC 50 (nM) 1.2 N/A N/A Details Marimastat Interstitial collagenase IC 50 (nM) 0.78 N/A N/A Details Marimastat Matrilysin IC 50 (nM) 4.1 N/A N/A Details Marimastat Neutrophil collagenase IC 50 (nM) 0.47 N/A N/A Details Marimastat Stromelysin-1 IC 50 (nM) 14 N/A N/A Details