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

Woodruff, T. M., Pollitt, S., Proctor, L. M., Stocks, S. Z., Manthey, H. D., Williams, H. M., Mahadevan, I. B., Shiels, I. A. and Taylor, S. M. (2005) Increased potency of a novel complement factor 5a receptor antagonist in a rat model of inflammatory bowel disease. Journal of Pharmacology And Experimental Therapeutics, 314 2: 811-817. doi:10.1124/jpet.105.086835

Author Woodruff, T. M.
Pollitt, S.
Proctor, L. M.
Stocks, S. Z.
Manthey, H. D.
Williams, H. M.
Mahadevan, I. B.
Shiels, I. A.
Taylor, S. M.
Title Increased potency of a novel complement factor 5a receptor antagonist in a rat model of inflammatory bowel disease
Journal name Journal of Pharmacology And Experimental Therapeutics   Check publisher's open access policy
ISSN 0022-3565
Publication date 2005-01-01
Year available 2005
Sub-type Article (original research)
DOI 10.1124/jpet.105.086835
Open Access Status Not yet assessed
Volume 314
Issue 2
Start page 811
End page 817
Total pages 7
Place of publication Bethesda
Publisher Amer Soc Pharmacology Experimental Therapeutics
Language eng
Subject C1
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.
Keyword Pharmacology & Pharmacy
Ischemia-reperfusion Injury
C5a Receptor
Polymorphonuclear Leukocytes
Activated Complement
Q-Index Code C1
Institutional Status UQ

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Created: Wed, 15 Aug 2007, 16:02:51 EST