title: Nonpeptide bradykinin B2 receptor antagonists: conversion of rodent-selective bradyzide analogues into potent, orally-active human bradykinin B2 receptor antagonists.
abstract: The 1-(2-nitrophenyl)thiosemicarbazide (TSC) derivative, (S)-1-[4-(4-benzhydrylthiosemicarbazido)-3-nitrobenzenesulfonyl]pyrrolidine-2-carboxylic acid [2-[(2-dimethylaminoethyl)methylamino]ethyl]amide (bradyzide; (S)-4), was recently disclosed as a novel, potent, orally active nonpeptide bradykinin (BK) B2 receptor antagonist. The compound inhibited the specific binding of [3H]BK to NG108-15 cell membrane preparations (rodent neuroblastoma-glioma) expressing B2 receptors with a K(i) of 0.5 +/- 0.2 nM. Compound (S)-4 also demonstrated oral efficacy against Freund's complete adjuvant (FCA)-induced mechanical hyperalgesia in rats with an ED50 value of 0.84 micromol/kg. After we optimized the terminal binding determinants projecting from the TSC framework, we found that it was possible to replace the potentially toxicophoric nitro and divalent sulfur moieties with only a 15-fold loss in binding affinity ((S)-14a). However, bradyzide and its congeners were found to have much lower affinities for cloned human B2 receptors, expressed in Cos-7 cells. The hitherto synthesized TSC series was screened against the human B2 receptor, and the dibenzosuberane (DBS) pharmacophore emerged as the key structural requirement for potency. Incorporation of this group resulted in a series of derivatives ((S)-14d,e and 19b-d) with K(i) ranges of 10.7-176 nM in NG108-15 cells (expressing the rodent B2 receptor) and 0.79-253 nM in Cos-7 cells (expressing the human B2 receptor). There was no evidence of agonist activity with any of the nonpeptides in any of the cell lines tested. In vivo, oral administration of compound 19c reversed FCA-induced and turpentine-induced mechanical hyperalgesia in rodents with ED50 values of 0.027 and 0.32 micromol/kg, respectively. The selectivity profiles of compounds (S)-14f and (S)-14g were also assessed to determine the conformational and/or steric preferences of the double-ring arrangement. The affinity of (S)-14 g for the human B2 receptor suggested that it may be a hydrophobic interaction with the ethane bridge of the DBS moiety that accounts for the increased potency of compounds (S)-14d,e and 19b,c at this receptor, by favoring a binding mode inaccessible to the unsubstituted diphenylmethyl derivative, (S)-4.
authors.affiliation: Novartis Institute for Medical Sciences, 5 Gower Place, London WC1E 6BS, England. ed.dziadulewicz@pharma.novartis.com
authors.forename: Edward K
authors.initials: EK
authors.lastname: Dziadulewicz
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ritchie
authors.forename: Allan
authors.initials: A
authors.lastname: Hallett
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Snell
authors.forename: John W
authors.initials: JW
authors.lastname: Davies
authors.forename: Roger
authors.initials: R
authors.lastname: Wrigglesworth
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Dunstan
authors.forename: Graham C
authors.initials: GC
authors.lastname: Bloomfield
authors.forename: Gillian S
authors.initials: GS
authors.lastname: Drake
authors.forename: Peter
authors.initials: P
authors.lastname: McIntyre
authors.forename: Michael C
authors.initials: MC
authors.lastname: Brown
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Burgess
authors.forename: Wai
authors.initials: W
authors.lastname: Lee
authors.forename: Clare
authors.initials: C
authors.lastname: Davis
authors.forename: Mohammed
authors.initials: M
authors.lastname: Yaqoob
authors.forename: Steve B
authors.initials: SB
authors.lastname: Phagoo
authors.forename: Elsa
authors.initials: E
authors.lastname: Phillips
authors.forename: Martin N
authors.initials: MN
authors.lastname: Perkins
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Campbell
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Davis
authors.forename: Humphrey P
authors.initials: HP
authors.lastname: Rang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy; D065168:Bradykinin Receptor Antagonists; D002460:Cell Line; D005260:Female; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D008958:Models, Molecular; D010812:Physical Stimulation; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043782:Receptor, Bradykinin B2; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014425:Turpentine
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D065168:Bradykinin Receptor Antagonists; D011759:Pyrrolidines; D043782:Receptor, Bradykinin B2; D013882:Thiosemicarbazones; C406475:bradyzide; D014425:Turpentine