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: H J Showell, M J Conklyn, R Alpert, G P Hingorani, K F Wright, M A Smith, E Stam, E D Salter, D N Scampoli, S Meltzer, L A Reiter, K Koch, A D Piscopio, S R Cortina, A Lopez-Anaya, E R Pettipher, A J Milici, R J Griffiths
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 285 Issue 3 Pg. 946-54 (Jun 1998) ISSN: 0022-3565 [Print] United States
• PMID: 9618393 (Publication Type: Journal Article)

Chemical References

• Cell Adhesion Molecules
• Chemotactic Factors
• Chromans
• Interleukin-1
• Macrophage-1 Antigen
• Prostaglandins
• Leukotriene B4
• Collagen
• Zymosan
• CP 195543

Topics

• Animals
• Arthritis (chemically induced, prevention & control)
• Cell Adhesion Molecules (drug effects, metabolism)
• Chemotactic Factors (metabolism)
• Chemotaxis (drug effects)
• Chromans (chemistry, pharmacology)
• Collagen
• Drug Evaluation, Preclinical
• Humans
• Interleukin-1 (metabolism)
• Leukotriene B4 (antagonists & inhibitors)
• Macrophage-1 Antigen (drug effects)
• Mice
• Mice, Inbred BALB C
• Monocytes (drug effects, metabolism)
• Neutrophils (drug effects, physiology)
• Prostaglandins (biosynthesis)
• Spleen (drug effects, metabolism)
• Zymosan (adverse effects)