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

Abstract

Leukotriene B4 (LTB4) 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 LTA4 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 LTB4. 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 α-, β-, and γ-amino acid analogues that are potent inhibitors of the LTA4 hydrolase enzyme and demonstrated good oral activity in a mouse ex vivo whole blood LTB4 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.