Synthesis of Potent Leukotriene A₄ Hydrolase Inhibitors. Identification of 3-[Methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic Acid

Abstract

Leukotriene B(4) (LTB(4)) is a potent, proinflammatory mediator involved in the pathogenesis of a number of diseases including inflammatory bowel disease, psoriasis, rheumatoid arthritis, and asthma. The enzyme LTA(4) hydrolase represents an attractive target for pharmacological intervention in these disease states, since the action of this enzyme is the rate-limiting step in the production of LTB(4). Our previous efforts focused on the exploration of a series of analogues related to screening hit SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) and resulted in the identification of potent, orally active inhibitors such as 2. Additional structure-activity relationship studies around this structural class resulted in the identification of a series of alpha-, beta-, and gamma-amino acid analogues that are potent inhibitors of the LTA(4) hydrolase enzyme and demonstrated good oral activity in a mouse ex vivo whole blood LTB(4) production assay. The efforts leading to the identification of clinical candidate SC-57461A (8d, 3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid) are described.

Mechanisms of Intimal Hyperplasia Learned from a Murine Carotid Artery Ligation Model

“…In contrast, recent work by Funk's group showed that 5-LO deficiency did not affect the formation of lipid-rich lesions in apoE deficient mice [39]. More recently, we used a selective LTA 4 H inhibitor, SC-57461A [40,41], at a dose of 30 mg/kg twice per day subcutaneously in the apoE deficient mice with CAL and treated with Ang II. Consistent with Funk's report, our results also showed that a LTA 4 H inhibitor failed to attenuate ligation-induced vascular remodeling in apoE deficient mice (Fig.…”

The Interrelationship between Leukotriene B4 and Leukotriene-A4-Hydrolase in Collagen/Adjuvant-Induced Arthritis in Rats

“…LTB4 is a potent proinflammatory lipid mediator synthesized by cells of the immune system and stimulates the production of several cytokines [10]. LT synthetic route is known to have three critical factors.…”

“…LTD4 is then cleaved by dipeptidases to form LTE4. Finally, the third factor is related to the activity of LTA4 hydrolase (LTA4H), which generates LTB4 by hydrolysis of LTA4 [10, 11]. LTA4H activity is known to be exerted by two bifunctional zinc metalloenzymes, EC 3.3.2.6, the canonical LTA4H [12], and EC 3.4.11.6 (basic aminopeptidase) [13, 14].…”

Efeitos do veneno de Apis mellifera e do metotrexato sobre peptidases do plasma, do líquido e membrana sinoviais e de leucócitos circulantes em ratos com artrite induzida por colágeno tipo II.

“…A LTA 4 hidrolase é uma enzima ubíqua (GRICE et al, 2008;HAEGGSTRÖM;THOLANDER;WETTERHOLM, 2007;MURPHY e GIJÓN, 2007) altamente específica para o LTA 4 , convertendo-o a LTB 4 (HAEGGSTRÖM; THOLANDER; WETTERHOLM, 2007;MURPHY e GIJÓN, 2007;PENNING et al, 2002). O LTB 4 é produzido por diversas células imunocompetentes, como neutrófilos e macrófagos, estimula diversas citocinas (PENNING et al, 2002), ativa células inflamatórias, como neutrófilos, macrófagos, células T e B (GRICE et al 2008;KIRKLAND et al, 2008), e é um mediador inflamatório potente que amplifica diversas doenças inflamatórias, como a AR (GRICE et al 2008;LIANG et al, 2007;PENNING et al, 2002).…”

“…Devido à grande importância do LTB 4 em estados inflamatórios, diversos estudos buscam um inibidor seletivo para a LTA 4 hidrolase (GRICE et al, 2008;KIRKLAND et al, 2008;PENNING et al, 2002). Apesar da importância da atividade LTA4 hidrolase em processos inflamatórios, a atuação dessa atividade na artrite não será abordada no presente trabalho, pois a medida dessa atividade envolve outra metodologia (HPLC) e outros reagentes específicos e de custo vultoso.…”