RT Journal Article SR Electronic T1 Pharmacological, Pharmacokinetic, and Primate Analgesic Efficacy Profile of the Novel Bradykinin B1 Receptor Antagonist ELN441958 JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 619 OP 630 DO 10.1124/jpet.107.120352 VO 322 IS 2 A1 Jon E. Hawkinson A1 Balazs G. Szoke A1 Albert W. Garofalo A1 Dennis S. Hom A1 Hongbing Zhang A1 Mark Dreyer A1 Juri Y. Fukuda A1 Linda Chen A1 Bhushan Samant A1 Stellanie Simmonds A1 Karla P. Zeitz A1 Angie Wadsworth A1 Anna Liao A1 Raymond A. Chavez A1 Wes Zmolek A1 Lany Ruslim A1 Michael P. Bova A1 Ryan Holcomb A1 Eduardo R. Butelman A1 Mei-Chuan Ko A1 Annika B. Malmberg YR 2007 UL http://jpet.aspetjournals.org/content/322/2/619.abstract AB The bradykinin B1 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 B1 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 B1 agonist ligand [3H]desArg10-kallidin ([3H]DAKD) to IMR-90 human fibroblast membranes with high affinity (Ki = 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 B1 over B2 receptors. Antagonism of agonist-induced calcium responses at B1 receptors from different species indicated that ELN441958 is selective for primate over rodent B1 receptors with a rank order potency (KB, nanomolar) of human (0.12 ± 0.02) ∼ 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 B1 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 ED50 ∼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 B1 receptor antagonist exhibiting high oral bioavailability and potent systemic efficacy in rhesus monkey inflammatory pain. The American Society for Pharmacology and Experimental Therapeutics