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Pre-clinical pharmacology of ICI D2138, a potent orally-active non-redox inhibitor of 5-lipoxygenase
| Content Provider | Scilit |
|---|---|
| Author | McMillan, R. M. Spruce, K. E. Crawley, G. C. Walker, E. R. H. Foster, S. J. |
| Copyright Year | 1992 |
| Description | Journal: British Journal of Pharmacology 1. This paper describes the pre-clinical pharmacology of ICI D2138, a potent orally-active non-redox inhibitor of 5-lipoxygenase which is undergoing clinical evaluation. 2. ICI D2138 potently inhibited leukotriene synthesis in murine peritoneal macrophages (IC50 = 3 nM) and human blood (IC50 = 20 nM). In human and dog blood, ICI D2138 did not inhibit thromboxane B2 synthesis at a concentration of 500 microM, thus the selectivity ratio (cyclo-oxygenase: 5-lipoxygenase) was greater than 20,000. In contrast, zileuton (a 5-lipoxygenase inhibitor also undergoing clinical evaluation) exhibited a selectivity ratio of 15-100. 3. ICI D2138 potently and dose-dependently inhibited ex vivo leukotriene B4 (LTB4) synthesis by rat blood with ED50 values of 0.9, 4.0 and 80.0 mg kg-1 p.o. at 3, 10 and 20 h respectively after dosing. Similar activity was observed for inhibition of LTB4 production in a zymosan-inflamed rat air pouch model. Zileuton produced ED50 values of 5 and 20 mg kg-1 at 3 and 10 h respectively. 4. Oral administration of 1, 3 or 10 mg kg-1 ICI D2138 to dogs produced maximal inhibition of ex vivo LTB4 synthesis by blood for 5, 9 and 31 h respectively. A dose of 5 mg kg-1 p.o. of zileuton caused maximal inhibition of LTB4 for 24 h. 5. Oral administration of 10 mg kg-1 ICI D2138 caused total inhibition of LTB4 production in zymosan-inflamed rabbit knee joint. 6. Topical administration of ICI D2138 to rabbit skin caused a dose-related inhibition of arachidonic acid-induced plasma extravasation with an ID30 of 1.08 nmol per site.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Related Links | http://europepmc.org/articles/pmc1907929?pdf=render http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.1992.tb13404.x/pdf |
| Ending Page | 1047 |
| Page Count | 6 |
| Starting Page | 1042 |
| e-ISSN | 14765381 |
| DOI | 10.1111/j.1476-5381.1992.tb13404.x |
| Journal | British Journal of Pharmacology |
| Issue Number | 4 |
| Volume Number | 107 |
| Language | English |
| Publisher | Wiley-Blackwell |
| Publisher Date | 1992-12-01 |
| Access Restriction | Open |
| Subject Keyword | Journal: British Journal of Pharmacology Medicinal Chemistry 5‐lipoxygenase Inhibitor Anti‐inflammatory Allergic Bronchospasm Inflammatory Diseases |
| Content Type | Text |
| Resource Type | Article |
