CGS 22745: a selective orally active inhibitor of 5-lipoxygenase.
CGS 22745, and aralkyl hydroxamic acid, inhibited 5-hydroxyeicosatetraenoic acid (5-HETE) and leukotriene B4 (LTB4) synthesis in guinea pig leukocytes (IC50 = 0.6 microM). The compound did not appreciably affect cyclooxygenase (ram seminal vesicles), 12-lipoxygenase and thromboxane synthase (human platelets) or 15-lipoxygenase (human neutrophils). CGS 22745 inhibited A23187-induced formation of LTB4 in blood (IC50's of 4.3, 0.56 and 3.2 microM for human, dog and rat, respectively). At 1 mg/kg i.v. in dogs, it caused 96% inhibition of A23187-stimulated LTB4 formation ex vivo after 5 min. Its effective biological half-life was greater than 160 min. In dogs at 3 and 10 mg/kg p.o., CGS 22745 inhibited ex vivo A23187-stimulated LTB4 formation at 3 hr by 48% and 97%, respectively. The inhibition persisted up to 6 hr (26% at 3 mg/kg; 49% at 10 mg/kg). CGS 22745 (3, 10 and 30 mg/kg p.o.) inhibited exudate formation, mononuclear cells and PMN accumulation in a dose-dependent manner during the late phase (48 and 72 hr) of carrageenan-induced pleurisy in the rat.
Kimble
E
E
Research Dept., CIBA-GEIGY Corp., Summit, NJ 07901.
Kowalski
T
T
White
D
D
Raychauduri
A
A
Pastor
G
G
Chertock
H
H
Lee
W
W
Neale
R
R
Hamdan
A
A
Wasley
J
J
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism; D001682:Biological Availability; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D000001:Calcimycin / Q000494:pharmacology; D004285:Dogs; D006168:Guinea Pigs; D006207:Half-Life; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D007975:Leukotriene B4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D010998:Pleurisy / Q000517:prevention & control; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012756:Sheep
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006877:Hydroxamic Acids; D016859:Lipoxygenase Inhibitors; D011758:Pyrroles; C073115:CGS 22745; D007975:Leukotriene B4; D016718:Arachidonic Acid; D000001:Calcimycin