title: Pyrrolidine and piperidine analogues of SC-57461A as potent, orally active inhibitors of leukotriene A(4) hydrolase.
abstract: The synthesis and biological evaluation of a series of functionalized pyrrolidine- and piperidine-containing analogues of our lead LTA(4) hydrolase inhibitor, SC-57461A, is described. A number of compounds showed excellent potency in our in vitro screens and several demonstrated good oral activity in a mouse ex vivo assay. These efforts led to the identification of SC-56938 (14) as a potent, orally active inhibitor of LTA(4) hydrolase.
authors.affiliation: Department of Medicinal Chemistry, Pharmacia Corporation, Skokie, IL 60077, USA. thomas.d.penning@pharmacia.com
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Penning
authors.forename: Nizal S
authors.initials: NS
authors.lastname: Chandrakumar
authors.forename: Bipin N
authors.initials: BN
authors.lastname: Desai
authors.forename: Stevan W
authors.initials: SW
authors.lastname: Djuric
authors.forename: Alan F
authors.initials: AF
authors.lastname: Gasiecki
authors.forename: Chi-Dean
authors.initials: CD
authors.lastname: Liang
authors.forename: Julie M
authors.initials: JM
authors.lastname: Miyashiro
authors.forename: Mark A
authors.initials: MA
authors.lastname: Russell
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Askonas
authors.forename: James K
authors.initials: JK
authors.lastname: Gierse
authors.forename: Elizabeth I
authors.initials: EI
authors.lastname: Harding
authors.forename: Maureen K
authors.initials: MK
authors.lastname: Highkin
authors.forename: James F
authors.initials: JF
authors.lastname: Kachur
authors.forename: Suzanne H
authors.initials: SH
authors.lastname: Kim
authors.forename: Doreen
authors.initials: D
authors.lastname: Villani-Price
authors.forename: E Yvonne
authors.initials: EY
authors.lastname: Pyla
authors.forename: Nayereh S
authors.initials: NS
authors.lastname: Ghoreishi-Haack
authors.forename: Walter G
authors.initials: WG
authors.lastname: Smith
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D010880:Piperidines; D011759:Pyrrolidines; C104311:SC 57461; C474036:SC56938; D015091:beta-Alanine; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase