- LTA4 Hydrolase inhibitors
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The present invention provides compounds of the formula Ar1-Q-Ar2-Y-R-Z and pharmaceutically acceptable salts thereof wherein Ar1 and Ar2 are optionally substituted aryl moieties, Z is an optionally substituted nitrogen-containing moiety which may be an acyclic, cyclic or bicyclic amine or an optionally substituted monocyclic or bicyclic nitrogen-containing heteroaromatic moiety; Q is a linking group capable of linking two aryl groups; R is an alkylene moiety; Y is a linking moiety capable of linking an aryl group to an alkylene moiety and wherein Z is bonded to R through a nitrogen atom. The compounds and pharmaceutical compositions of the present invention are useful in the treatment of inflammatory diseases which are mediated by LTB4 production, such as proriasis, ulcerative colitis, IBD and asthma.
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- Structure-activity relationship studies on 1-[2-(4- phenylphenoxy)ethyl]pyrrolidine (SC-22716), a potent inhibitor of leukotriene A4 (LTA4) hydrolase
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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.
- 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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p. 721 - 735
(2007/10/03)
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