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Drug-Target Interaction

Drug

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PubChem ID:119031
Structure:
Synonyms:
(2R,3S)-N-[(2S)-3,3-dimethyl-1-methylamino-1-oxobutan-2-yl]-N',3-dihydroxy-2-(2-methylpropyl)butanediamide
(2S,3R)-3-(((1S)-2,2-Dimethyl-1-(methylcarbamoxy)propyl)carboyl)-2-hydroxy-5-methylhexanohydroxamic acid
(2S,3R)-3-(((1S)-2,2-Dimethyl-1-(methylcarbamoyl)propyl)carbamoyl)-2-hydroxy-5-methylhexanohydroxamic acid
(2S,3R)-N(4)-[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-N(1),2-dihydroxy-3-(2-methylpropyl)butanediamide
154039-60-8
BB 2516
BB-2516
Butanediamide,
Butanediamide, N(sup 4)-(2,2-dimethyl-1-((methylamino)carbonyl)propyl)-N(sup 1),2-dihydroxy-3-(2-methylpropyl)-, (2S-(N(sup 4)(R*),2R*,3S*))-
Butanediamide, N4-((1S)-2,2-dimethyl-1-((methylamino)carbonyl)propyl)-N1,2-dihydroxy-3-(2-methylpropyl)-, (2S,3R)-
Butanediamide, N4-(2,2-dimethyl-1-((methylamino)carbonyl)propyl)-N1,2-dihydroxy-3-(2-methylpropyl)-, (2S-(N4(R*),2R*,3S*))-
C100342
C15H29N3O5
CHEBI:50662
D03795
DB00786
LS-45634
Marimastat
Marimastat (USAN/INN)
Marimastat [USAN]

Target

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Uniprot ID:Q9Y354_HUMAN
Synonyms:
Matrix metalloproteinase 9
EC-Numbers:3.4.24.35
Organism:Homo sapiens
Human
PDB IDs:-

Binding Affinities:

Ki: Kd:Ic 50:Ec50/Ic50:
----

References:

9626215
Phase I trial of Marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer.. S Wojtowicz-Praga; J Torri; M Johnson; V Steen; J Marshall; E Ness; R Dickson; M Sale; H S Rasmussen; T A Chiodo; M J Hawkins (1998) Journal of clinical oncology : official journal of the American Society of Clinical Oncology display abstract
PURPOSE: This phase I study was performed to evaluate the safety and pharmacokinetics of escalating doses of Marimastat (British Biotech, Inc, Oxford, United Kingdom) in patients with advanced malignancies and to determine the phase II recommended dose to be used in subsequent studies. PATIENTS AND METHODS: A standard phase I design was used in this study, in which consecutive groups of three patients were treated with escalating doses of the study drug. Marimastat was administered orally at 25, 50, or 100 mg twice daily to consecutive groups of patients with advanced lung cancer. An additional three patients were added at the highest dose studied (100 mg orally twice daily) to assess whether the inflammatory polyarthitis observed at that dose level can be prevented by a concurrent administration of nonsteroidal antiinflammatory drugs (NSAIDS) and/or low-dose corticosteroids. Blood was drawn for safety monitoring, pharmacokinetic analysis, and plasma levels of metalloproteinase (MMP)-2 and MMP-9 (determined by zymography). A total of 12 patients were studied. RESULTS: The most significant toxicity at the highest dose studied (100 mg orally twice daily) was a symptomatic inflammatory polyarthritis that persisted for up to 8 weeks after discontinuation of the study drug and was dose-limiting. The estimated plasma elimination half-life of Marimastat was 4 to 5 hours. The mean maximum concentration (Cmax) at a reasonably well-tolerated dose (50 mg orally twice daily) was 196 ng/mL and was reached within 1 to 2 hours (Tmax) after administration. Areas under the curve (AUC) tended to correlate with the dose of Marimastat. Zymographic analysis of peripheral-blood ratios of activated proenzymatic forms of MMP-2 and -9 did not show any consistent patterns of change in MMP levels or in a degree of their activation during the course of treatment. CONCLUSION: Marimastat was well absorbed from the gastrointestinal tract, with high levels of the study drug detected in plasma within hours after drug administration. Plasma concentrations of Marimastat achieved at dose levels 2 and 3 (50 mg and 100 mg orally twice daily) were substantially higher than those required for MMP inhibition in vitro. The dose-limiting toxicity (DLT) was severe inflammatory polyarthritis, which seemed to be a cumulative toxicity.