Asunto(s)
Proteínas Portadoras/química , Ésteres del Colesterol/sangre , Glicoproteínas , Propanolaminas/síntesis química , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/sangre , Proteínas de Transferencia de Ésteres de Colesterol , Cristalografía por Rayos X , Humanos , Técnicas In Vitro , Propanolaminas/sangre , Propanolaminas/química , EstereoisomerismoRESUMEN
Leukotriene B(4) (LTB(4)) is a pro-inflammatory mediator that has been implicated in the pathogenesis of a number of diseases including inflammatory bowel disease (IBD) and psoriasis. Since the action of LTA(4) hydrolase is the rate-limiting step for LTB(4) production, this enzyme represents an attractive pharmacological target for the suppression of LTB(4) production. From an in-house screening program, SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) was identified as a potent inhibitor of LTA(4) hydrolase. Structure-activity relationship (SAR) studies around this structural class resulted in the identification of a number of novel, potent inhibitors of LTA(4) hydrolase, several of which demonstrated good oral activity in a mouse ex vivo whole blood assay.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Epóxido Hidrolasas/antagonistas & inhibidores , Pirrolidinas/síntesis química , Administración Oral , Animales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Técnicas In Vitro , Leucotrieno B4/biosíntesis , Leucotrieno B4/sangre , Masculino , Ratones , Pirrolidinas/química , Pirrolidinas/farmacología , Relación Estructura-ActividadRESUMEN
The novel amino acid 8(S)-amino-2(R)-methyl-7-oxononanoic acid (1) was isolated from the soil-borne microorganism Streptomyces diastaticus during our screening for inhibitors of leukotriene-A4 hydrolase (LTA4H), a requisite enzyme in the biosynthesis of the potent inflammatory mediator leukotriene-B4 (LTB4). The structure of 1 was determined by detailed spectroscopic analyses and is related to 7-keto-8-aminopelargonic acid (2), a biosynthetic precursor of biotin. The relative potency of 1 (LTA4H IC50 = 0.6 microM) warranted further biological studies.
Asunto(s)
Inhibidores Enzimáticos/aislamiento & purificación , Epóxido Hidrolasas/antagonistas & inhibidores , Ácidos Grasos/aislamiento & purificación , Streptomyces/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Biotina/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ácidos Grasos/química , Ácidos Grasos/farmacología , Humanos , Leucotrieno B4/biosíntesis , Leucotrieno B4/sangre , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Conejos , Streptomyces/química , Tromboxano B2/biosíntesis , Tromboxano B2/sangreRESUMEN
Haloenol lactones are potent mechanism-based inhibitors of a novel class of calcium-independent phospholipases A2 which have been implicated as the enzymic mediators of membrane dysfunction during myocardial ischemia (Hazen, S. L.; et al. J. Biol. Chem. 1991, 266, 7227-7232). Herein we demonstrate that the ring size, hydrophobic group, and cryptic electrophile in the haloenol lactone moiety are important and modifiable determinants of the inhibitory potency of haloenol lactone-mediated inhibition of calcium-independent phospholipase A2. Direct comparisons between haloenol lactone-mediated inhibition of calcium-independent phospholipase A2 and the absence of inhibition with calcium-dependent phospholipase A2 further underscore the marked differences in the catalytic strategy employed by these two classes of intracellular phospholipases A2.