title: Carboxy-substituted cinnamides: a novel series of potent, orally active LTB4 receptor antagonists.
abstract: A series of carboxy-substituted cinnamides were investigated as antagonists of the human cell surface leukotriene B4 (LTB4) receptor. Binding was determined through measurement of [3H]LTB4 displacement from human neutrophils. Receptor antagonism was confirmed through a functional assay, which measures inhibition of Ca2+ release in human neutrophils. Potent antagonists were discovered through optimization of a random screening hit, a p-(alpha-methylbenzyloxy)cinnamide, having low-micromolar activity. Substantial improvement of in vitro potency was realized by the attachment of a carboxylic acid moiety to the cinnamide phenyl ring through a flexible tether, leading to identification of compounds with low-nanomolar potency. Modification of the benzyloxy substituent, either through ortho-substitution on the benzyloxy phenyl group or through replacement of the ether oxygen with a methylene or sulfur atom, produced achiral antagonists of equal or greater potency. The most potent compounds in vitro were assayed for oral activity using the arachidonic acid-induced mouse ear edema model of inflammation. Several compounds in this series were found to significantly inhibit edema formation and myeloperoxidase activity in this model up to 17 h after oral administration. Representatives of this series have been shown to be potent and long-acting orally active inhibitors of the LTB4 receptor.
authors.affiliation: Arthritis and Bone Metabolism Research, Novartis Pharmaceuticals Corporation, 556 Morris Avenue, Summit, New Jersey 07901, USA.
authors.forename: P D
authors.initials: PD
authors.lastname: Greenspan
authors.forename: R A
authors.initials: RA
authors.lastname: Fujimoto
authors.forename: P J
authors.initials: PJ
authors.lastname: Marshall
authors.forename: A
authors.initials: A
authors.lastname: Raychaudhuri
authors.forename: K E
authors.initials: KE
authors.lastname: Lipson
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.forename: R A
authors.initials: RA
authors.lastname: Doti
authors.forename: D E
authors.initials: DE
authors.lastname: Coppa
authors.forename: L
authors.initials: L
authors.lastname: Zhu
authors.forename: R
authors.initials: R
authors.lastname: Pelletier
authors.forename: S
authors.initials: S
authors.lastname: Uziel-Fusi
authors.forename: R H
authors.initials: RH
authors.lastname: Jackson
authors.forename: M H
authors.initials: MH
authors.lastname: Chin
authors.forename: B L
authors.initials: BL
authors.lastname: Kotyuk
authors.forename: J J
authors.initials: JJ
authors.lastname: Fitt
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002934:Cinnamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004423:Ear; D004487:Edema / Q000188:drug therapy; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D002934:Cinnamates; D018102:Receptors, Leukotriene B4; D002118:Calcium