Increased potency of a novel complement factor 5a receptor antagonist in a rat model of inflammatory bowel disease.

Abstract

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.

• Authors: Trent M Woodruff, Sandra Pollitt, Lavinia M Proctor, Shelli Z Stocks, Helga D Manthey, Hua M Williams, Indumathy B Mahadevan, Ian A Shiels, Stephen M Taylor
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 314 Issue 2 Pg. 811-7 (Aug 2005) ISSN: 0022-3565 [Print] United States
• PMID: 15879003 (Publication Type: Journal Article)

Chemical References

• AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg)
• Peptides, Cyclic
• Receptors, Complement
• hydrocinnamate-cyclo(ornithyl-prolyl-cyclohexylalanyl-tryptophyl-arginyl)
• Complement C5a
• Trinitrobenzenesulfonic Acid

Topics

• Animals
• Biological Availability
• Biotransformation
• Complement C5a (metabolism)
• Digestive System (metabolism)
• Eating (drug effects)
• Edema (chemically induced, pathology, prevention & control)
• Female
• Humans
• Inflammatory Bowel Diseases (chemically induced, drug therapy, pathology)
• Intestinal Mucosa (pathology)
• Peptides, Cyclic (pharmacokinetics, pharmacology, therapeutic use)
• Rats
• Rats, Wistar
• Receptors, Complement (antagonists & inhibitors)
• Trinitrobenzenesulfonic Acid
• Ulcer (chemically induced, pathology, prevention & control)
• Weight Loss