Rational design, synthesis and structure-activity relationships of a cyclic succinate series of TNF-alpha converting enzyme inhibitors. Part 2: lead optimization.
Bioorg Med Chem Lett
; 13(24): 4299-304, 2003 Dec 15.
Article
en En
| MEDLINE
| ID: mdl-14643313
ABSTRACT
Modifications of the lead TACE inhibitor 1 (N-hydroxy-trans-2-[[4-(4-quinolinyloxymethyl)anilinyl]carbonyl]-1-cyclohexanecarboxamide) at the cyclohexyl ring and the quinoline moiety led to the identification of a series of piperidine containing TACE inhibitors with potent activity in the inhibition of TNF-alpha release in the whole blood assay (WBA). The most potent analogue IM491 [N-hydroxy-(5S,6S)-1-methyl-6-[[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl]-5-piperidinecarboxamide] exhibited an IC(50) value of 20 nM in WBA with excellent selectivity over MMP-1, -2 and -9 and is orally bioavailable with an F value of 43% in beagle dogs.
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Banco de datos:
MEDLINE
Asunto principal:
Succinatos
/
Metaloendopeptidasas
/
Inhibidores Enzimáticos
Tipo de estudio:
Prognostic_studies
Idioma:
En
Año:
2003
Tipo del documento:
Article