Assuntos
Proteínas de Transporte/química , Ésteres do Colesterol/sangue , Glicoproteínas , Propanolaminas/síntese química , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/sangue , Proteínas de Transferência de Ésteres de Colesterol , Cristalografia por Raios X , Humanos , Técnicas In Vitro , Propanolaminas/sangue , Propanolaminas/química , EstereoisomerismoRESUMO
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.
Assuntos
Inibidores Enzimáticos/síntese química , Epóxido Hidrolases/antagonistas & inibidores , Pirrolidinas/síntese química , Administração Oral , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Técnicas In Vitro , Leucotrieno B4/biossíntese , Leucotrieno B4/sangue , Masculino , Camundongos , Pirrolidinas/química , Pirrolidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores Enzimáticos/isolamento & purificação , Epóxido Hidrolases/antagonistas & inibidores , Ácidos Graxos/isolamento & purificação , Streptomyces/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Biotina/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Ácidos Graxos/química , Ácidos Graxos/farmacologia , Humanos , Leucotrieno B4/biossíntese , Leucotrieno B4/sangue , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Coelhos , Streptomyces/química , Tromboxano B2/biossíntese , Tromboxano B2/sangueRESUMO
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.
