The preclinical pharmacological profile of the potent and selective leukotriene B4 antagonist CP-195543.
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.
Showell
H J
HJ
Department of Cancer, Immunology and Infectious Diseases, Pfizer Inc, Groton, Connecticut, USA.
Conklyn
M J
MJ
Alpert
R
R
Hingorani
G P
GP
Wright
K F
KF
Smith
M A
MA
Stam
E
E
Salter
E D
ED
Scampoli
D N
DN
Meltzer
S
S
Reiter
L A
LA
Koch
K
K
Piscopio
A D
AD
Cortina
S R
SR
Lopez-Anaya
A
A
Pettipher
E R
ER
Milici
A J
AJ
Griffiths
R J
RJ
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
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