Pre-clinical pharmacology of ICI D2138, a potent orally-active non-redox inhibitor of 5-lipoxygenase.
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. Zileuton was approximately 40 times less potent.7. Oral anti-inflammatory activity was assessed in an arachidonic acid-induced mouse ear oedema model in animals treated with indomethacin to block pro-inflammatory prostanoids. ICI D2138, given orally, caused dose-dependent inhibition of oedema with an approximate ID50 of 1.8 mg kg'. Zileuton was approximately 10 times less potent.8. ICI D2138 caused a dose-dependent inhibition of antigen-induced broncho-constriction in guineapigs with an approximate ID50 of 0.1 mg kg-', i.v. Zileuton was approximately 10 times less potent.9. In view of the pharmacological profile described here, ICI D2138 has the potential to provide improved clinical efficacy compared to existing lipoxygenase inhibitors such as zileuton.
McMillan
R M
RM
ICI Pharmaceuticals, Alderley Park, Macclesfield, Cheshire.
Spruce
K E
KE
Crawley
G C
GC
Walker
E R
ER
Foster
S J
SJ
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy; D007719:Knee Joint; D007975:Leukotriene B4 / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D011714:Pyrans / Q000008:administration & dosage / Q000494:pharmacology*; D015363:Quinolones / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D013929:Thromboxane B2 / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016859:Lipoxygenase Inhibitors; D011714:Pyrans; D015363:Quinolones; C075799:ICI D2138; D007975:Leukotriene B4; D016718:Arachidonic Acid; D013929:Thromboxane B2; C063449:zileuton; D006918:Hydroxyurea