CGS 22745: a selective orally active inhibitor of 5-lipoxygenase.

Abstract

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.

• Authors: E Kimble, T Kowalski, D White, A Raychauduri, G Pastor, H Chertock, W Lee, R Neale, A Hamdan, J Wasley
• Journal: Agents and actions (Agents Actions) Vol. 34 Issue 1-2 Pg. 125-8 (Sep 1991) ISSN: 0065-4299 [Print] Switzerland
• PMID: 1665286 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Hydroxamic Acids
• Lipoxygenase Inhibitors
• Pyrroles
• CGS 22745
• Leukotriene B4
• Arachidonic Acid
• Calcimycin

Topics

• Administration, Oral
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Arachidonic Acid (metabolism)
• Biological Availability
• Blood Platelets (drug effects, enzymology)
• Calcimycin (pharmacology)
• Dogs
• Guinea Pigs
• Half-Life
• Humans
• Hydroxamic Acids (administration & dosage, pharmacokinetics, pharmacology)
• In Vitro Techniques
• Leukocytes (drug effects, metabolism)
• Leukotriene B4 (biosynthesis)
• Lipoxygenase Inhibitors (administration & dosage, pharmacokinetics, pharmacology)
• Neutrophils (drug effects, enzymology)
• Pleurisy (prevention & control)
• Pyrroles (administration & dosage, pharmacokinetics, pharmacology)
• Rats
• Sheep