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NEUROPHARMACOLOGY

Pharmacological, Pharmacokinetic, and Primate Analgesic Efficacy Profile of the Novel Bradykinin B₁ Receptor Antagonist ELN441958

Elan Pharmaceuticals, South San Francisco, California (J.E.H., B.G.S., A.W.G., D.S.H., H.Z., M.D., J.Y.F., L.C., B.S., S.S., K.P.Z., A.W., A.L., R.A.C., W.Z., L.R., M.P.B., R.H., A.B.M.); Laboratory on the Biology of Addictive Diseases, The Rockefeller University, New York, New York (E.R.B.); and Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (M.-C.K.)

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 (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 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 (K_B, 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.

Address correspondence to: Dr. Jon E. Hawkinson, Lead Discovery and Optimization, Elan Pharmaceuticals, 800 Gateway Blvd., South San Francisco, CA 94080. E-mail: jon.hawkinson{at}earthlink.net