title: Pharmacological, pharmacokinetic, and primate analgesic efficacy profile of the novel bradykinin B1 Receptor antagonist ELN441958.
abstract: 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.
authors.affiliation: Lead Discovery and Optimization, Elan Pharmaceuticals, South San Francisco, CA 94080, USA. jon.hawkinson@earthlink.net
authors.forename: Jon E
authors.initials: JE
authors.lastname: Hawkinson
authors.forename: Balazs G
authors.initials: BG
authors.lastname: Szoke
authors.forename: Albert W
authors.initials: AW
authors.lastname: Garofalo
authors.forename: Dennis S
authors.initials: DS
authors.lastname: Hom
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
authors.forename: Mark
authors.initials: M
authors.lastname: Dreyer
authors.forename: Juri Y
authors.initials: JY
authors.lastname: Fukuda
authors.forename: Linda
authors.initials: L
authors.lastname: Chen
authors.forename: Bhushan
authors.initials: B
authors.lastname: Samant
authors.forename: Stellanie
authors.initials: S
authors.lastname: Simmonds
authors.forename: Karla P
authors.initials: KP
authors.lastname: Zeitz
authors.forename: Angie
authors.initials: A
authors.lastname: Wadsworth
authors.forename: Anna
authors.initials: A
authors.lastname: Liao
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Chavez
authors.forename: Wes
authors.initials: W
authors.lastname: Zmolek
authors.forename: Lany
authors.initials: L
authors.lastname: Ruslim
authors.forename: Michael P
authors.initials: MP
authors.lastname: Bova
authors.forename: Ryan
authors.initials: R
authors.lastname: Holcomb
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Butelman
authors.forename: Mei-Chuan
authors.initials: MC
authors.lastname: Ko
authors.forename: Annika B
authors.initials: AB
authors.lastname: Malmberg
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000700:Analgesics / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065169:Bradykinin B1 Receptor Antagonists; D002118:Calcium / Q000378:metabolism; D002351:Carrageenan / Q000633:toxicity; D002460:Cell Line; D002463:Cell Membrane Permeability; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D007609:Kallidin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D008253:Macaca mulatta; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D009271:Naltrexone / Q000494:pharmacology; D009288:Naproxen / Q000494:pharmacology / Q000627:therapeutic use; D009292:Narcotic Antagonists; D051381:Rats; D043783:Receptor, Bradykinin B1 / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D013141:Spiro Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D014162:Transfection
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000700:Analgesics; D065169:Bradykinin B1 Receptor Antagonists; C522836:ELN441958; D009292:Narcotic Antagonists; D043783:Receptor, Bradykinin B1; D013141:Spiro Compounds; C082229:bradykinin, Lys-Leu(8)-desArg(9)-; C024626:bradykinin, des-Arg(9)-; D007609:Kallidin; D009288:Naproxen; D009271:Naltrexone; C052787:kallidin, des-Arg(10)-; D002351:Carrageenan; D001920:Bradykinin; D002118:Calcium