Structure−Activity Relationship Studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine (SC-22716), a Potent Inhibitor of Leukotriene A4 (LTA4) Hydrolase

Leukotriene B4 (LTB4) 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 LTA4 hydrolase is the rate-limiting step for LTB4 production, this enzyme represents an attractive p...

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Veröffentlicht in:Journal of medicinal chemistry 2000-02, Vol.43 (4), p.721-735
Hauptverfasser: Penning, Thomas D, Chandrakumar, Nizal S, Chen, Barbara B, Chen, Helen Y, Desai, Bipin N, Djuric, Stevan W, Docter, Stephen H, Gasiecki, Alan F, Haack, Richard A, Miyashiro, Julie M, Russell, Mark A, Yu, Stella S, Corley, David G, Durley, Richard C, Kilpatrick, Brian F, Parnas, Barry L, Askonas, Leslie J, Gierse, James K, Harding, Elizabeth I, Highkin, Maureen K, Kachur, James F, Kim, Suzanne H, Krivi, Gwen G, Villani-Price, Doreen, Pyla, E. Yvonne, Smith, Walter G, Ghoreishi-Haack, Nayereh S
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Sprache:eng
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Zusammenfassung:Leukotriene B4 (LTB4) 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 LTA4 hydrolase is the rate-limiting step for LTB4 production, this enzyme represents an attractive pharmacological target for the suppression of LTB4 production. From an in-house screening program, SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) was identified as a potent inhibitor of LTA4 hydrolase. Structure−activity relationship (SAR) studies around this structural class resulted in the identification of a number of novel, potent inhibitors of LTA4 hydrolase, several of which demonstrated good oral activity in a mouse ex vivo whole blood assay.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm990496z