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Structure-activity relationship studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine (SC-22716), a potent inhibitor of leukotriene A(4) (LTA(4)) hydrolase. 2000
T D Penning, and
N S Chandrakumar, and
B B Chen, and
H Y Chen, and
B N Desai, and
S W Djuric, and
S H Docter, and
A F Gasiecki, and
R A Haack, and
J M Miyashiro, and
M A Russell, and
S S Yu, and
D G Corley, and
R C Durley, and
B F Kilpatrick, and
B L Parnas, and
L J Askonas, and
J K Gierse, and
E I Harding, and
M K Highkin, and
J F Kachur, and
S H Kim, and
G G Krivi, and
D Villani-Price, and
E Y Pyla, and
W G Smith
Departments of Medicinal Chemistry, Structure-Activity Screening Program, Inflammatory Diseases Research, and Molecular Pharmacology, Searle Research and Development, Monsanto Company, Skokie, Illinois 60077, USA. thomas.d.penning@monsanto.com
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.
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