title: Identification of benzofuran central cores for the inhibition of leukotriene A(4) hydrolase.
abstract: Leukotrienes (LT's) are known to play a physiological role in inflammatory immune response. Leukotriene A(4) hydrolase (LTA(4)H) is a cystolic enzyme that stereospecifically catalyzes the transformation of LTA(4) to LTB(4). LTB(4) is a known pro-inflammatory mediator. This paper describes the identification and synthesis of substituted benzofurans as LTH(4)H inhibitors. The benzofuran series demonstrated reduced mouse and human whole blood LTB(4) levels in vitro and led to the identification one analog for advanced profiling. Benzofuran 28 showed dose responsive target engagement and provides a useful tool to explore a LTA(4)H inhibitor for the treatment of inflammatory diseases, such as asthma and inflammatory bowel disease (IBD).
authors.affiliation: Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA. weccles@its.jnj.com
authors.forename: Wendy
authors.initials: W
authors.lastname: Eccles
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Blevitt
authors.forename: Jamila N
authors.initials: JN
authors.lastname: Booker
authors.forename: Christa C
authors.initials: CC
authors.lastname: Chrovian
authors.forename: Shelby
authors.initials: S
authors.lastname: Crawford
authors.forename: Aimee Rose
authors.initials: AR
authors.lastname: de Leon
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Deng
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fourie
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Grice
authors.forename: Krystal
authors.initials: K
authors.lastname: Herman
authors.forename: Lars
authors.initials: L
authors.lastname: Karlsson
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Kearney
authors.forename: Alice
authors.initials: A
authors.lastname: Lee-Dutra
authors.forename: Jimmy
authors.initials: J
authors.lastname: Liang
authors.forename: Rosa
authors.initials: R
authors.lastname: Luna
authors.forename: Dan
authors.initials: D
authors.lastname: Pippel
authors.forename: Navin
authors.initials: N
authors.lastname: Rao
authors.forename: Jason P
authors.initials: JP
authors.lastname: Riley
authors.forename: Alejandro
authors.initials: A
authors.lastname: Santillán
authors.forename: Brad
authors.initials: B
authors.lastname: Savall
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Tanis
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Xue
authors.forename: Arlene L
authors.initials: AL
authors.lastname: Young
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001572:Benzofurans; D004791:Enzyme Inhibitors; D004851:Epoxide Hydrolases; C105430:benzofuran; C043134:leukotriene A4 hydrolase