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1.
Bioorg Med Chem Lett ; 11(20): 2775-8, 2001 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-11591521

RESUMEN

Heterocyclic ureas, such as N-3-thienyl N'-aryl ureas, have been identified as novel inhibitors of raf kinase, a key mediator in the ras signal transduction pathway. Structure-activity relationships were established, and the potency of the screening hit was improved 10-fold to IC(50)=1.7 microM. A combinatorial synthesis approach enabled the identification of a breakthrough lead (IC(50)=0.54 microM) for a second generation series of heterocyclic urea raf kinase inhibitors.


Asunto(s)
Proteínas Proto-Oncogénicas c-raf/antagonistas & inhibidores , Urea/análogos & derivados , Urea/farmacología , Relación Estructura-Actividad , Urea/síntesis química , Urea/química
2.
Bioorg Med Chem Lett ; 8(17): 2369-74, 1998 Sep 08.
Artículo en Inglés | MEDLINE | ID: mdl-9873543

RESUMEN

A combinatorial library of piperazinediones has been prepared by automated parallel solid-phase synthesis. The five-step reaction protocol makes use of Kaiser oxime resin, to enable cleavage from the polymeric support concomitant with an intramolecular displacement reaction, under very mild conditions. The methodology was also successfully extended to the preparation of the seven-membered ring homologs, diazepinediones.


Asunto(s)
Azepinas/síntesis química , Bases de Datos como Asunto , Diseño de Fármacos , Piperazinas/química , Piperazinas/síntesis química , Resinas de Plantas , Azepinas/química , Indicadores y Reactivos , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Relación Estructura-Actividad
3.
J Antibiot (Tokyo) ; 47(11): 1195-201, 1994 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-8002381

RESUMEN

Two new peptides, a diketopiperazine of N-methyltyrosine (1) and a tetrapeptide containing N-methyltyrosine (2), were isolated from an actinomycete strain Streptomyces griseus. These compounds inhibit the enzyme calpain in the micromolar range and were characterized on the basis of spectroscopic analysis, amino acid analysis and sequencing. The structure of the tetrapeptide N-methyltyrosyl-N-methyltyrosyl-leucyl-alanine (2), was also confirmed by total synthesis.


Asunto(s)
Calpaína/antagonistas & inhibidores , Oligopéptidos/aislamiento & purificación , Piperazinas/aislamiento & purificación , Streptomyces griseus/metabolismo , Tirosina/análogos & derivados , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Inhibidores Enzimáticos/farmacología , Espectroscopía de Resonancia Magnética , Oligopéptidos/química , Oligopéptidos/farmacología , Piperazinas/química , Piperazinas/farmacología , Tirosina/química , Tirosina/aislamiento & purificación , Tirosina/farmacología
4.
Biochemistry ; 33(9): 2373-9, 1994 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-8117696

RESUMEN

D-Arg0[Hyp3,Thi5,D-Tic7,Oic8]bradykinin (HOE-140) is a potent (Ki = 0.11 nM) inhibitor of [3H]bradykinin binding to bradykinin B2 receptors found on human IMR-90 fetal lung fibroblasts. During the synthesis of this compound, we isolated and unambiguously identified the L-Tic7 stereoisomer (WIN 65365), which exhibits a 2000-fold lower binding affinity (Ki = 130 nM) than HOE-140 to the bradykinin receptor. A similar decrease in potency is observed for WIN 65365 inhibition of bradykinin-stimulated 45Ca2+ efflux from IMR-90 cells. Both HOE-140 and WIN 65365 appear to be competitive antagonists at the IMR-90 bradykinin receptor. This is the first documentation of bradykinin binding and functional antagonist activity by a bradykinin peptide analogue with an L amino acid replacing Pro7. In an attempt to rationalize the differences in binding affinities of HOE-140 and WIN 65365, a conformational analysis of the peptides was undertaken using annealed molecular dynamics (AMD). Conformational analysis of HOE-140 reveals a strong preference for the formation of a type II' beta-turn in the carboxy-terminal region. Analogous modeling of WIN 65365 reveals that its conformation is strikingly different from HOE-140 in that the four carboxy-terminal residues of WIN 65365 do not form a beta-turn. These differences in low-energy conformations between the two peptides may lead to a better understanding of the molecular interaction of antagonists with the bradykinin receptor.


Asunto(s)
Bradiquinina/análogos & derivados , Bradiquinina/antagonistas & inhibidores , Receptores de Bradiquinina/metabolismo , Secuencia de Aminoácidos , Bradiquinina/síntesis química , Bradiquinina/química , Calcio/metabolismo , Línea Celular , Humanos , Técnicas In Vitro , Modelos Moleculares , Datos de Secuencia Molecular , Conformación Proteica , Estereoisomerismo , Relación Estructura-Actividad , Termodinámica
5.
J Med Chem ; 37(3): 356-63, 1994 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-7508512

RESUMEN

Two novel cyclic heptapeptides, peptides 1a and 1c, were isolated from an Aspergillus flavipes culture, originally isolated from soil, and their structures established by chemical and spectroscopic evidence. Peptide 1a contains a new amino acid, 3-prenyl-beta-hydroxytyrosine, and is a competitive antagonist to substance P at the human NK1 receptor, with an inhibitor affinity constant (Ki) of 8 +/- 4 microM. Methylation of 1a gave the monomethyl derivative 1b, which is a more potent competitive antagonist, with a Ki of 0.12 +/- 0.03 microM at the human NK1 receptor. Herein we report the structure determinations of 1a and 1c, and some structure-activity results. Several analogs of 1a were prepared by derivatization and synthesis. Structure-activity results for these analogs confirmed that the 3-prenyl-beta-hydroxytyrosine moiety is critical for the biological potency of 1a and 1b.


Asunto(s)
Aspergillus/química , Dihidroxifenilalanina/análogos & derivados , Péptidos Cíclicos/química , Sustancia P/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Unión Competitiva , Dihidroxifenilalanina/análisis , Cobayas , Humanos , Íleon/fisiología , Datos de Secuencia Molecular , Estructura Molecular , Contracción Muscular/efectos de los fármacos , Péptidos Cíclicos/metabolismo , Péptidos Cíclicos/farmacología , Receptores de Neuroquinina-1/metabolismo , Relación Estructura-Actividad
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