Structure-activity relationship studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine (SC-22716), a potent inhibitor of leukotriene A(4) (LTA(4)) hydrolase

  • J Med Chem. 2000 Feb 24;43(4):721-35. doi: 10.1021/jm990496z.
T D Penning  1 ,  N S Chandrakumar ,  B B Chen ,  H Y Chen ,  B N Desai ,  S W Djuric ,  S H Docter ,  A F Gasiecki ,  R A Haack ,  J M Miyashiro ,  M A Russell ,  S S Yu ,  D G Corley ,  R C Durley ,  B F Kilpatrick ,  B L Parnas ,  L J Askonas ,  J K Gierse ,  E I Harding ,  M K Highkin ,  J F Kachur ,  S H Kim ,  G G Krivi ,  D Villani-Price ,  E Y Pyla ,  W G Smith
Affiliations
  • 1. Departments of Medicinal Chemistry, Structure-Activity Screening Program, Inflammatory Diseases Research, and Molecular Pharmacology, Searle Research and Development, Monsanto Company, Skokie, Illinois 60077, USA. [email protected]
PMID: 10691697 DOI: 10.1021/jm990496z
Abstract

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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