title: Structure-activity relationship studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine (SC-22716), a potent inhibitor of leukotriene A(4) (LTA(4)) hydrolase.
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.
authors.affiliation: 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
authors.forename: T D
authors.initials: TD
authors.lastname: Penning
authors.forename: N S
authors.initials: NS
authors.lastname: Chandrakumar
authors.forename: B B
authors.initials: BB
authors.lastname: Chen
authors.forename: H Y
authors.initials: HY
authors.lastname: Chen
authors.forename: B N
authors.initials: BN
authors.lastname: Desai
authors.forename: S W
authors.initials: SW
authors.lastname: Djuric
authors.forename: S H
authors.initials: SH
authors.lastname: Docter
authors.forename: A F
authors.initials: AF
authors.lastname: Gasiecki
authors.forename: R A
authors.initials: RA
authors.lastname: Haack
authors.forename: J M
authors.initials: JM
authors.lastname: Miyashiro
authors.forename: M A
authors.initials: MA
authors.lastname: Russell
authors.forename: S S
authors.initials: SS
authors.lastname: Yu
authors.forename: D G
authors.initials: DG
authors.lastname: Corley
authors.forename: R C
authors.initials: RC
authors.lastname: Durley
authors.forename: B F
authors.initials: BF
authors.lastname: Kilpatrick
authors.forename: B L
authors.initials: BL
authors.lastname: Parnas
authors.forename: L J
authors.initials: LJ
authors.lastname: Askonas
authors.forename: J K
authors.initials: JK
authors.lastname: Gierse
authors.forename: E I
authors.initials: EI
authors.lastname: Harding
authors.forename: M K
authors.initials: MK
authors.lastname: Highkin
authors.forename: J F
authors.initials: JF
authors.lastname: Kachur
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.forename: G G
authors.initials: GG
authors.lastname: Krivi
authors.forename: D
authors.initials: D
authors.lastname: Villani-Price
authors.forename: E Y
authors.initials: EY
authors.lastname: Pyla
authors.forename: W G
authors.initials: WG
authors.lastname: Smith
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000097:blood; D008297:Male; D051379:Mice; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011759:Pyrrolidines; C405046:SC 27716; D007975:Leukotriene B4; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase