Pharmacological, Pharmacokinetic, and Primate Analgesic Efficacy Profile of the Novel Bradykinin B1 Receptor Antagonist ELN441958
| Autor: | Angie Wadsworth, Lany Ruslim, Bhushan Samant, Dennis S. Hom, Linda Chen, Hongbing Zhang, Juri Y Fukuda, Mei-Chuan Ko, Anna Liao, Stellanie Simmonds, Karla P. Zeitz, Wes Zmolek, Raymond A. Chavez, Michael P. Bova, Balazs G. Szoke, Mark Dreyer, Albert W. Garofalo, Annika B. Malmberg, Eduardo R. Butelman, Ryan Holcomb, Jon E. Hawkinson |
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| Rok vydání: | 2007 |
| Předmět: |
Agonist
Cell Membrane Permeability medicine.drug_class Narcotic Antagonists Bradykinin Biology Pharmacology Carrageenan Receptor Bradykinin B1 Transfection Cell Line Mice chemistry.chemical_compound Naproxen Species Specificity medicine Animals Humans Potency Spiro Compounds ATP Binding Cassette Transporter Subfamily B Member 1 Receptor Benzamide Mice Knockout Analgesics Molecular Structure Fibroblasts Kallidin Receptor antagonist Ligand (biochemistry) Macaca mulatta Naltrexone Rats Bradykinin B1 Receptor Antagonists chemistry Opioid Hyperalgesia Microsomes Liver Molecular Medicine Calcium medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 322:619-630 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | The bradykinin B(1) receptor plays a critical role in chronic pain and inflammation, although efforts to demonstrate efficacy of receptor antagonists have been hampered by species-dependent potency differences, metabolic instability, and low oral exposure of current agents. The pharmacology, pharmacokinetics, and analgesic efficacy of the novel benzamide B(1) receptor antagonist 7-chloro-2-[3-(9-pyridin-4-yl-3,9-diazaspiro[5.5]undecanecarbonyl)phenyl]-2,3-dihydro-isoindol-1-one (ELN441958) is described. ELN441958 competitively inhibited the binding of the B(1) agonist ligand [(3)H]desArg(10)-kallidin ([(3)H]DAKD) to IMR-90 human fibroblast membranes with high affinity (K(i) = 0.26 +/- 0.02 nM). ELN441958 potently antagonized DAKD (but not bradykinin)-induced calcium mobilization in IMR-90 cells, indicating that it is highly selective for B(1) over B(2) receptors. Antagonism of agonist-induced calcium responses at B(1) receptors from different species indicated that ELN441958 is selective for primate over rodent B(1) receptors with a rank order potency (K(B), nanomolar) of human (0.12 +/- 0.02) approximately rhesus monkey (0.24 +/- 0.01) > rat (1.5 +/- 0.4) > mouse (14 +/- 4). ELN441958 had good permeability and metabolic stability in vitro consistent with high oral exposure and moderate plasma half-lives in rats and rhesus monkeys. Because ELN441958 is up to 120-fold more potent at primate than at rodent B(1) receptors, it was evaluated in a primate pain model. ELN441958 dose-dependently reduced carrageenan-induced thermal hyperalgesia in a rhesus monkey tail-withdrawal model, with an ED(50) approximately 3 mg/kg s.c. Naltrexone had no effect on the antihyperalgesia produced by ELN441958, indicating a lack of involvement of opioid receptors. ELN441958 is a novel small molecule bradykinin B(1) receptor antagonist exhibiting high oral bioavailability and potent systemic efficacy in rhesus monkey inflammatory pain. |
| Databáze: | OpenAIRE |
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