title: Identification of a potent, selective, and orally active leukotriene a4 hydrolase inhibitor with anti-inflammatory activity.
abstract: LTA 4H is a ubiquitously distributed 69 kDa zinc-containing cytosolic enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA 4H stereospecifically catalyzes the transformation of the unstable epoxide LTA 4 to the diol LTB 4, a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, and T cells. Inhibiting the formation of LTB 4 is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease (IBD), asthma, and atherosclerosis. We developed a pharmacophore model using a known inhibitor manually docked into the active site of LTA 4H to identify a subset of compounds for screening. From this work we identified a series of benzoxazole, benzthiazole, and benzimidazole inhibitors. SAR studies resulted in the identification of several potent inhibitors with an appropriate cross-reactivity profile and excellent PK/PD properties. Our efforts focused on further profiling JNJ 27265732, which showed encouraging efficacy in a disease model relevant to IBD.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA. cgrice@prdus.jnj.com
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Grice
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Tays
authors.forename: Brad M
authors.initials: BM
authors.lastname: Savall
authors.forename: Jianmei
authors.initials: J
authors.lastname: Wei
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Butler
authors.forename: Frank U
authors.initials: FU
authors.lastname: Axe
authors.forename: Scott D
authors.initials: SD
authors.lastname: Bembenek
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fourie
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dunford
authors.forename: Katherine
authors.initials: K
authors.lastname: Lundeen
authors.forename: Fawn
authors.initials: F
authors.lastname: Coles
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Xue
authors.forename: Jason P
authors.initials: JP
authors.lastname: Riley
authors.forename: Kacy N
authors.initials: KN
authors.lastname: Williams
authors.forename: Lars
authors.initials: L
authors.lastname: Karlsson
authors.forename: James P
authors.initials: JP
authors.lastname: Edwards
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002384:Catalysis; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase