title: Pharmacological profile of CR3465, a new leukotriene CysLT1 receptor antagonist with broad anti-inflammatory activity.
abstract: CR3465 (L-Tyrosine, N-[(2-quinolinyl)carbonyl]-O-(7-fluoro-2-quinolinylmethyl) sodium salt) is a potent antagonist of [3H]leukotriene D4 ([3H]LTD4) binding to guinea pig lung preparations, its Ki (4.7+/-0.7 nM) being comparable with that of montelukast (5.6+/-0.6 nM). In tracheal strips from standard or ovalbumin-sensitized guinea pigs, CR3465 caused parallel rightward shifts in the concentration-response curves obtained with either LTD4 or antigen (pA(2), 8.74 and 8.15). Intravenous (i.v.) administration of the agent both antagonized (ED50, 9.9+/-1.9 microg/kg) and reverted LTD4 -induced bronchoconstriction of anesthetized guinea pigs. CR3465 reduced inflammatory infiltrates in the bronchoalveolar lavage fluid after antigen challenge of sensitized animals, and proved also active in inhibiting phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) activities exhibited by human platelets and neutrophils (IC50, 2.01+/-0.07 and 4.7+/-0.5 microM). In line with properties shown by phosphodiesterase inhibitors, CR3465 reduced the contractile response of guinea pig airways to histamine and decreased N-formyl-Met-Leu-Phe (fMLP)-induced degranulation of human neutrophils (IC50, 13.8 microM). Oral administration (20 mg/kg) of the compound in rats produced a significant (37%) ex vivo inhibition of tumor necrosis factor-alpha (TNF-alpha) release from lipopolysaccharide-stimulated whole blood. Pharmacokinetic data in the rat demonstrated approximately 100% bioavailability of the agent. We conclude that CR3465 represents a potent leukotriene CysLT1 receptor antagonist with enhanced effects, being also useful for counteracting spasmogenic and inflammatory stimuli other than those elicited by cysteinyl-leukotrienes (Cys-LTs).
authors.affiliation: Rotta Research Laboratorium S.p.A., Pharmacology and Toxicology Department, Via Valosa di Sopra 7/9-20052 Monza (MI), Italy. Flora.Ferrari@rotta.com
authors.forename: Flora
authors.initials: F
authors.lastname: Ferrari
authors.forename: Laura
authors.initials: L
authors.lastname: Mennuni
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Caselli
authors.forename: Tiziano
authors.initials: T
authors.lastname: Zanelli
authors.forename: Francesco
authors.initials: F
authors.lastname: Makovec
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D000893:Anti-Inflammatory Agents; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016084:Bronchoconstriction / Q000187:drug effects; D015550:Cell Degranulation / Q000187:drug effects; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects; D010276:Parasympatholytics / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D018077:Receptors, Leukotriene; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D006633:Histamine Antagonists; C499418:L-tyrosine, N-((2-quinolinyl)carbonyl)-O-(7-fluoro-2-quinolinylmethyl) sodium salt; D008565:Membrane Proteins; D010276:Parasympatholytics; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; D018077:Receptors, Leukotriene; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; D009240:N-Formylmethionine Leucyl-Phenylalanine; D017998:Leukotriene D4; D006632:Histamine; D009195:Peroxidase; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C083169:leukotriene D4 receptor