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.
Leukotriene (LT) B 4 is an inflammatory mediator that has been implicated in the pathogenesis of various diseases, including inflammatory bowel disease and psoriasis. As the rate-limiting step for LTB 4 production, LTA 4 hydrolase represents an attractive target for therapeutic agents that interfere with LTB 4 production. In the present study we evaluated a chemically novel compound designated phenoxy]propyl]amino]propanoic acid HCl) as an inhibitor of LTA 4 hydrolase. Pharmacological comparisons are made to its free acid SC-57461. SC-57461A is a potent competitive inhibitor of recombinant human LTA 4 hydrolase when either LTA 4 (IC 50 ϭ 2.5 nM, K i ϭ 23 nM) or peptide substrates (IC 50 ϭ 27 nM) are used. In human whole blood, the IC 50 for calcium ionophore-induced LTB 4 production was 49 nM, indicative of good cell penetration. Whole blood production of the cyclooxygenase metabolite thromboxane B 2 was not affected. SC-57461A was also active in several other species, including mouse, rat, dog, and rhesus monkey. The data indicate that SC-57461A is a potent and selective inhibitor of LTA 4 hydrolase.
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.
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