title: 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.affiliation: Promics Pty. Ltd., The University of Queensland, Brisbane, QLD 4072 Australia.
authors.forename: Trent M
authors.initials: TM
authors.lastname: Woodruff
authors.forename: Sandra
authors.initials: S
authors.lastname: Pollitt
authors.forename: Lavinia M
authors.initials: LM
authors.lastname: Proctor
authors.forename: Shelli Z
authors.initials: SZ
authors.lastname: Stocks
authors.forename: Helga D
authors.initials: HD
authors.lastname: Manthey
authors.forename: Hua M
authors.initials: HM
authors.lastname: Williams
authors.forename: Indumathy B
authors.initials: IB
authors.lastname: Mahadevan
authors.forename: Ian A
authors.initials: IA
authors.lastname: Shiels
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Taylor
mesh_terms: D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D015936:Complement C5a / Q000378:metabolism*; D004064:Digestive System / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D004487:Edema / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D007413:Intestinal Mucosa / Q000473:pathology; D010456:Peptides, Cyclic / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D011951:Receptors, Complement / Q000037:antagonists & inhibitors*; D014302:Trinitrobenzenesulfonic Acid; D014456:Ulcer / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D015431:Weight Loss
chemical_list: C438957:AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg); D010456:Peptides, Cyclic; D011951:Receptors, Complement; C504156:hydrocinnamate-cyclo(ornithyl-prolyl-cyclohexylalanyl-tryptophyl-arginyl); D015936:Complement C5a; D014302:Trinitrobenzenesulfonic Acid