Pharmacological, pharmacokinetic, and primate analgesic efficacy profile of the novel bradykinin B1 receptor antagonist ELN441958

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 [3H]desArg(10-)kallidin ([3H]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) similar to rhesus monkey (0.24 +/- 0.01) similar to 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 similar to 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.