Imidazo[1,2-a]pyrimidines as functionally selective and orally bioavailable GABA-α2/α3 binding site agonists for the treatment of anxiety disorders

被引:130
作者
Goodacre, SC
Street, LJ
Hallett, DJ
Crawforth, JM
Kelly, S
Owens, AP
Blackaby, WP
Lewis, RT
Stanley, J
Smith, AJ
Ferris, P
Sohal, B
Cook, SM
Pike, A
Brown, N
Wafford, KA
Marshall, G
Castro, JL
Atack, JR
机构
[1] Merck Sharp & Dohme Res Labs, Ctr Res Neurosci, Dept Med Chem, Harlow CM20 2QR, Essex, England
[2] Merck Sharp & Dohme Res Labs, Ctr Res Neurosci, Dept Biochem, Harlow CM20 2QR, Essex, England
[3] Merck Sharp & Dohme Res Labs, Ctr Res Neurosci, Dept Pharmacol, Harlow CM20 2QR, Essex, England
关键词
D O I
10.1021/jm051065l
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of high-affinity GABA(A) agonists with good oral bioavailability in rat and dog and functional selectivity for or the GABA(A)alpha 2 and -alpha 3 subtypes is reported. The 7-trifluoroinethylimidazopyrimidine 14g and the 7-propan-2-olimidazopyrimidine 14k are anxiolytic in both conditioned and unconditioned animal models of anxiety with minimal sedation observed at full BZ binding site occupancy.
引用
收藏
页码:35 / 38
页数:4
相关论文
共 37 条
  • [1] The benzodiazepine binding site of GABAA receptors as a target for the development of novel anxiolytics
    Atack, JR
    [J]. EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2005, 14 (05) : 601 - 618
  • [2] Regional differences in the inhibition of mouse in vivo [3H]Ro 15-1788 binding reflect selectivity for α1 versus α2 and α3 subunit-containing GABAA receptors
    Atack, JR
    Smith, AJ
    Emms, F
    McKernan, RM
    [J]. NEUROPSYCHOPHARMACOLOGY, 1999, 20 (03) : 255 - 262
  • [3] ATACK JR, IN PRESS J PHARM EXP
  • [4] Barnard EA, 1998, PHARMACOL REV, V50, P291
  • [5] Comparison of benzodiazepine (BZ) receptor agonists in two rodent activity tests
    Bayley, PJ
    Bentley, GD
    Jackson, A
    Williamson, D
    Dawson, GR
    [J]. JOURNAL OF PSYCHOPHARMACOLOGY, 1996, 10 (03) : 206 - 213
  • [6] BLACKABY WP, 2002, Patent No. 02076983
  • [7] θ, a novel γ-aminobutyric acid type A receptor subunit
    Bonnert, TP
    McKernan, RM
    Farrar, S
    le Bourdellès, B
    Heavens, RP
    Smith, DW
    Hewson, L
    Rigby, MR
    Sirinathsinghji, DJS
    Brown, N
    Wafford, KA
    Whiting, PJ
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (17) : 9891 - 9896
  • [8] Pharmacological characterization of a novel cell line expressing human α4β3δ GABAA receptors
    Brown, N
    Kerby, J
    Bonnert, TP
    Whiting, PJ
    Wafford, KA
    [J]. BRITISH JOURNAL OF PHARMACOLOGY, 2002, 136 (07) : 965 - 974
  • [9] 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine:: A functionally selective γ-aminobutyric acidA (GABAA) α2/α3-subtype selective agonist that exhibits potent anxiolytic activity but is not sedating in animal models
    Carling, RW
    Madin, A
    Guiblin, A
    Russell, MGN
    Moore, KW
    Mitchinson, A
    Sohal, B
    Pike, A
    Cook, SM
    Ragan, IC
    McKernan, RM
    Quirk, K
    Ferris, P
    Marshall, G
    Thompson, SA
    Wafford, KA
    Dawson, GR
    Atack, JR
    Harrison, T
    Castro, JL
    Street, LJ
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (23) : 7089 - 7092
  • [10] 3-phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-α]phthalazines and analogues:: High-affinity γ-aminobutyric acid-A benzodiazepine receptor ligands with α2, α3, and α5-subtype binding selectivity over α1
    Carling, RW
    Moore, KW
    Street, LJ
    Wild, D
    Isted, C
    Leeson, PD
    Thomas, S
    O'Connor, D
    McKernan, RM
    Quirk, K
    Cook, SM
    Atack, JR
    Wafford, KA
    Thompson, SA
    Dawson, GR
    Ferris, P
    Castro, JL
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (07) : 1807 - 1822