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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Increased Potency of a Novel Complement Factor 5a Receptor Antagonist in a Rat Model of Inflammatory Bowel Disease

Promics Pty. Ltd., The University of Queensland, Brisbane, Australia

We have previously shown that complement factor 5a (C5a) plays a role in the pathogenesis of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats by using the selective, orally active C5a antagonist AcF-[OP(D-Cha)WR]. This study tested the efficacy and potency of a new C5a antagonist, hydrocinnamate (HC)-[OP(D-Cha)WR], which has limited intestinal lumenal metabolism, in this model of colitis. Analogs of AcF-[OP(D-Cha)WR] were examined for their susceptibility to alimentary metabolism in the rat using intestinal mucosal washings. One metabolically stable analog, HC-[OP(D-Cha)WR], was then evaluated pharmacokinetically and investigated at a range of doses (0.03–10 mg/kg/day p.o.) in the 8-day rat TNBS-colitis model, against the comparator drug AcF-[OP(D-Cha)WR]. Using various amino acid substitutions, it was determined that the AcF moiety of AcF-[OP(D-Cha)WR] was responsible for the metabolic instability of the compound in intestinal mucosal washings. The analog HC-[OP(D-Cha)WR], equiactive in vitro to AcF-[OP(D-Cha)WR], was resistant to intestinal metabolism, but it displayed similar oral bioavailability to AcF-[OP(D-Cha)WR]. However, in the rat TNBS-colitis model, HC-[OP(D-Cha)WR] was effective at reducing mortality, colon edema, colon macroscopic scores, and increasing food consumption and body weights, at 10- to 30-fold lower oral doses than AcF-[OP(D-Cha)WR]. These studies suggest that resistance to intestinal metabolism by HC-[OP(D-Cha)WR] may result in increased local concentrations of the drug in the colon, thus affording efficacy with markedly lower oral doses than AcF-[OP(D-Cha)WR] against TNBS-colitis. This large increase in potency and high efficacy of this compound makes it a potential candidate for clinical development against intestinal diseases such as inflammatory bowel disease.

Address correspondence to: Prof. Stephen M. Taylor, Promics Pty., Ltd., The University of Queensland, Brisbane, QLD 4072 Australia. E-mail: s.taylor{at}uq.edu.au

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