Platelet-activating factor antagonists

Platelet activating factor (PAF) has been identified as 1-0-alkyl-2-0-acetyl-sn-glycero-3-phosphocholine. Many different types of mammalian cells have been reported to release PAF upon stimulation. F. H. Chilton et al., Journal of Biochemistry, 257 5402-5407 (1982). 

Formula I is a naturally occurring derivative of the compound 6a,7,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-l- 

Non-psychoactive Derivatives of A6-THC-7-oic Acid which have Analgesic and Anti-inflammatory Properties 

Previous work with A6-Tetrahydrocannabinol [(3R,4R) 6a,7,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-l -ol, hereinafter referred to as A6-THC], has indicated that derivatives of this compound may prove clinically useful. The 7-carboxy derivative of A6-THC [A6-THC-7-oic acid] has been reported to be a non-psychoactive, potent antagonist to endogenous platelet activating factor and, thus, a useful treatment for PAF-induced disorders, such as asthma, systemic anaphylaxis, and septic shock. (U.S. Pat. No. 4,973,603, issued Nov. 27, 1990 to Sumner Burstein). Another derivative, (3S,4S)-7-hydroxy-A6-THC-l,l-dimethylheptyl, has been reported to possess analgesic and antiemetic activities. (U.S. Pat. No. 4,876,276). 

The present invention is generally directed to non-psychoactive derivatives of A6-THC-7-oic acid, which have been shown to be potent analgesic and anti-inflammatory agents and to possess leukocyte antiadhesion activities. The invention is further related to the use of these derivatives as therapeutic agents in the treatment of pain and tissue inflammation, especially that associated with long-term illnesses such as rheumatoid arthritis. 

---

D8. DeJoy, S. Q., Jeyaseelan, R., Torley, L. W., Pickett, W. C., Wissner, A., Wick, M. M., Oronsky, A. L., and Kerwar, S. S., Effect of CL 184,005, a platelet-activating factor antagonist in a murine model of Staphylococcus aureus-induced gram-positive sepsis. J. Infect. Dis. 169, 150-156... 

D22. Dirkes, K., Harris, B. H., Connolly, R. J., Schwaitzberg, S. D., Dinarello, C. A., and Gelfand, J. A., Platelet activating factor-antagonist improves survival in experimental staphylococcal septicemia. 7. Pediatr. Surg. 29, 1055-1057 (1994). 

K10. Klabunde, R. E., and Calvello, C., Inhibition of endotoxin-induced microvascular leakage by a platelet-activating factor antagonist and 5-lipoxygenase inhibitor. Shock 4, 368-372 (1995). 

Panetta, T., MarcheselH, V. L., Braquet, P., Spinnewyn, B. and Bazan, N. G. Effects of a platelet-activating factor antagonist (BN52021) on free fatty acids, diacylglycerols, polyphosphoinositides and blood flow in the gerbil brain Inhibition of ischemia-reperfusion induced cerebral injury. Biochem. Biophys. Res. Commun. 149 580-587,1987. 

The replacement of the polar head group of a range of piperazines by a 2-methylimidazo[4,5-f]pyridine group provided efficient orally active platelet-activating factor antagonists, for example, compounds 191-193 <1996JME487>. 

A platelet-activating factor, l-0-alkyl-2-(R)acetyl-sn-glyceryl-3-phosphocholine, is released in the presence of shock and ischemia. The platelet-activating factor antagonist can protect the heart and brain against ischemic injury. 

J3. Johnson, C. D., Kingsnorth, A. N., Imrie, C. W., McMahon, M. J., Neoptolemos, J. P., McKay, C., Toh, S. K., Skaife, P., Leeder, P. C., Wilson, P., Larvin, M., and Curtis, L. D., Double blind, randomised, placebo controlled study of a platelet activating factor antagonist, Lexipafant, in the treatment and prevention of organ failure in predicted severe acute pancreatitis. Gut 48, 62-69... 

Other platelet-activating factor antagonists consisting of 1,4-dihydropyridine derivatives, (III), were prepared by the authors (3) and used in treating neurological diseases. 

Braquet, P. The ginkgolides potent platelet-activating factor antagonists isolated from Ginkgo biloba L. chemistry, pharmacology and clinical applications. Drugs Future, 1987, 12 643-699. 

Prehn, J. H. Krieglstein, J. Platelet-activating factor antagonists reduce excitotoxic damage in cultured neurons from embryonic chick telencephalon and protect the rat hippocampus and neocortex from ischemic injury in vivo. J. Neurosci. Res., 1993, 34 179-188. 

Schifitto G, Sacktor N, Marder K, McDermott MP, McArthur JC, Kieburtz K, Small S, Epstein LG (1999) Randomized trial of the platelet-activating factor antagonist lexipafant in HIV-associated cognitive impairment. Neurological AIDS Research Consortium. Neurology 53 391-396. 

Kawaguchi A, Sugimoto K, Fujimura A. Preventive effect of platelet-activating factor antagonist, Y-24180, against cyclosporine-induced acute nephrotoxicity. Life Sci 2001 68 1181-1190. 

Burstein, S. Platelet Activating Factor Antagonist and Methods of Use Therefor 1990 US 4,973,603... 

Summers. J.B. etal. (1995) Platelet activating factor antagonists. Adv. Pharmacol.. 32.67-168. 

---