title: trans-3-Benzyl-4-hydroxy-7-chromanylbenzoic acid derivatives as antagonists of the leukotriene B4 (LTB4) receptor.
abstract: The SAR of a series of 2-(7-chromanyl)benzoic acids has been investigated with the aim of identifying potent and selective LTB4 receptor antagonists that maintain potency in complex biological fluids. We found optimal activity in derivatives with electron-withdrawing groups in the benzoic acid ring and with an unsubstituted C-3 benzyl group on the chromanol nucleus. While compounds containing a 3-(4-phenyl)benzyl chromanol substituent were potent LTB4 receptor antagonists, the increased lipophilicity imparted by the additional phenyl substituent led to decreased potency in the presence of plasma proteins. From among the potent compounds identified, CP-195543, the 5'-trifluoromethyl 3-benzyl chromanol, was selected for development.
authors.affiliation: Pfizer Inc, Central Research Division, Groton, CT 06340, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Reiter
authors.forename: K
authors.initials: K
authors.lastname: Koch
authors.forename: A D
authors.initials: AD
authors.lastname: Piscopio
authors.forename: H J
authors.initials: HJ
authors.lastname: Showell
authors.forename: R
authors.initials: R
authors.lastname: Alpert
authors.forename: M S
authors.initials: MS
authors.lastname: Biggers
authors.forename: R J
authors.initials: RJ
authors.lastname: Chambers
authors.forename: M J
authors.initials: MJ
authors.lastname: Conklyn
authors.forename: K
authors.initials: K
authors.lastname: Cooper
authors.forename: S R
authors.initials: SR
authors.lastname: Cortina
authors.forename: J N
authors.initials: JN
authors.lastname: Dibrino
authors.forename: B W
authors.initials: BW
authors.lastname: Dominy
authors.forename: C A
authors.initials: CA
authors.lastname: Farrell
authors.forename: G P
authors.initials: GP
authors.lastname: Hingorani
authors.forename: G J
authors.initials: GJ
authors.lastname: Martinelli
authors.forename: M
authors.initials: M
authors.lastname: Ramchandani
authors.forename: K F
authors.initials: KF
authors.lastname: Wright
mesh_terms: D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D016177:Macrophage-1 Antigen / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001565:Benzoates; D001798:Blood Proteins; D016177:Macrophage-1 Antigen; D018102:Receptors, Leukotriene B4