title: The preclinical pharmacological profile of the potent and selective leukotriene B4 antagonist CP-195543.
abstract: CP-195543 [(+)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid] is a structurally novel, selective and potent leukotriene B4 (LTB4) receptor antagonist. In vitro CP-195543 inhibited [3H]LTB4 binding to high-affinity LTB4 receptors on human neutrophils (HN) and murine spleen membranes with IC50 values of 6.8 nM (Ki = 4.9 nM) and 37.0 nM (Ki = 26.9 nM), respectively. CP-195543 inhibited human and mouse neutrophil chemotaxis mediated by LTB4 with IC50 values of 2.4 nM and 7.5 nM, respectively. Evidence of noncompetitive antagonist effects on the HN high-affinity LTB4 receptor was obtained by Scatchard analysis of [3H]LTB4 binding to and chemotaxis of HN to LTB4. Scatchard analyses of [3H]LTB4 binding to low-affinity receptors on HN indicated that CP-195543 acted as a competitive antagonist at this receptor, and inhibition of LTB4-mediated CD11b up-regulation on HN was inhibited competitively by CP-195543 (pA2 = 7.66). In whole blood, CP-195543 also blocked CD11b up-regulation on HN (pA2 = 7.12) and murine neutrophils (pA2 = 7.06) with a similar potency. LTB4-mediated CD11b up-regulation on human monocytes and eosinophils in whole blood were inhibited by CP-195543 with IC50 values of 270 nM and 420 nM, respectively. CP-195543 at 10 microM failed to inhibit HN chemotaxis and CD11b up-regulation mediated through alternative (i.e., complement fragment 5a, interleukin-8, platelet-activating factor) G-protein-coupled chemotactic factor receptors. In vivo, after oral administration, CP-195543 blocked LTB4-mediated neutrophil infiltration in guinea pig and murine skin with ED50 values of 0.1 mg/kg and 2.8 mg/kg p.o., respectively. When administered in osmotic pumps, CP-195543 reduced the clinical symptoms and attendant weight loss in an IL-1-exacerbated murine model of collagen-induced arthritis with half-maximal effects associated with plasma drug levels of 0.4 to 0.5 microg/ml. Collectively these data provide evidence of the in vitro potency and in vivo efficacy of a novel LTB4 antagonist and support its clinical evaluation in a variety of inflammatory diseases in man.
authors.affiliation: Department of Cancer, Immunology and Infectious Diseases, Pfizer Inc, Groton, Connecticut, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Showell
authors.forename: M J
authors.initials: MJ
authors.lastname: Conklyn
authors.forename: R
authors.initials: R
authors.lastname: Alpert
authors.forename: G P
authors.initials: GP
authors.lastname: Hingorani
authors.forename: K F
authors.initials: KF
authors.lastname: Wright
authors.forename: M A
authors.initials: MA
authors.lastname: Smith
authors.forename: E
authors.initials: E
authors.lastname: Stam
authors.forename: E D
authors.initials: ED
authors.lastname: Salter
authors.forename: D N
authors.initials: DN
authors.lastname: Scampoli
authors.forename: S
authors.initials: S
authors.lastname: Meltzer
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: S R
authors.initials: SR
authors.lastname: Cortina
authors.forename: A
authors.initials: A
authors.lastname: Lopez-Anaya
authors.forename: E R
authors.initials: ER
authors.lastname: Pettipher
authors.forename: A J
authors.initials: AJ
authors.lastname: Milici
authors.forename: R J
authors.initials: RJ
authors.lastname: Griffiths
mesh_terms: D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000517:prevention & control; D015815:Cell Adhesion Molecules / Q000187:drug effects / Q000378:metabolism; D002630:Chemotactic Factors / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D002839:Chromans / Q000737:chemistry / Q000494:pharmacology*; D003094:Collagen; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors*; D016177:Macrophage-1 Antigen / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D011453:Prostaglandins / Q000096:biosynthesis; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D015054:Zymosan / Q000009:adverse effects
chemical_list: D015815:Cell Adhesion Molecules; D002630:Chemotactic Factors; D002839:Chromans; D007375:Interleukin-1; D016177:Macrophage-1 Antigen; D011453:Prostaglandins; D007975:Leukotriene B4; D003094:Collagen; D015054:Zymosan; C112776:CP 195543