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)ethylpyrrolidine) 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 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-methyl3-4-(phenylmethyl)phenylpropylaminopropanoic acid) are described.
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