APPS November 2002 Meeting Abstract 2438

Activation of the complement system of plasma proteins can result in unregulated overproduction of potent proinflammatory complement factors, including the anaphylatoxin C5a. C5a is a key inflammatory mediator and immunomodulator, and exerts its effect after interaction with specific surface receptors on a number of different cell types, resulting in the release of other imflammatory mediators, including TNFα, IL-1, IL-6, IL-8, histamine, prostaglandins and leukotrienes, as well as reactive oxygen species. Activation of C5a has been implicated in a wide range of inflammatory disease states, including rheumatoid arthritis, adult respiratory distress syndrome, systemic lupus erythematosus, reperfusion injury, sepsis and ischaemic heart disease¹. C5a is therefore a viable target for the treatment of inflammatory diseases.

Promics Pty Ltd has developed cyclic, C-terminal derived analogues that selectively block the function of C5a by limiting binding to its receptors. PMX-53 has been selected as the leading C5a antagonist because of its potency against the target. The compound produces insurmountable antagonism and has been shown to be of effect at low concentrations in vitro using intact polymorphonuclear leukocytes from a number of different species. PMX-53 is effective in reducing clinical signs and inhibiting markers of inflammation in a number of different animal models of human disease, including adjuvant-induced arthritis, immune-complex mediated dermal inflammation and ischemia-reperfusion injury. The drug is effective when administered using a variety of routes, including intravenous, oral, subcutaneous and topical. A continuing program using rational drug design to develop analogues of PMX-53 with superior properties for oral or topical application is an integral part of Promics' philosophy. Amino acids within the cyclic molecule will be substituted in order to develop compounds with optimum activity, oral bioavailability, and pharmaceutic properties.