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

被引:151
作者
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
机构
[1] Merck Sharp & Dohme Res Labs, Neurosci Res Ctr, Dept Med Chem, Harlow CM20 2QR, Essex, England
[2] Merck Sharp & Dohme Res Labs, Neurosci Res Ctr, Dept Biochem, Harlow CM20 2QR, Essex, England
[3] Merck Sharp & Dohme Res Labs, Neurosci Res Ctr, Dept Pharmacol, Harlow CM20 2QR, Essex, England
关键词
D O I
10.1021/jm031020p
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Studies with our screening lead 5 and the literature compound 6 led to the identification of 6-benzyloxy-3-(4-methoxy)phenyl-1,2,4-triazolo[3,4-a]phthalazine 8 as a ligand with binding selectivity for the gamma-aminobutyric acid-A (GABA-A) alpha3- and alpha5-containing receptor subtypes over the GABA-A alpha1 subtype (K-i: alpha2 = 850 nM, alpha3 = 170 nM, alpha5 = 72 nM, alpha1 = 1400 nM). Early optimization studies identified the close analogue 10 (Ki: alpha2 = 16 nM, alpha3 = 41 nM, alpha5 = 38 nM, alpha1 = 280 nM) as a suitable lead for further study. High-affinity ligands were identified by replacing the 6-benzyloxy group of compound 10 with 2-pyridylmethoxy (compound 29), but binding selectivity was not enhanced (K-i: alpha2 = 1.7 nM, alpha3 = 0.71 nM, alpha5 = 0.33 nM, alpha1 = 2.7 nM). Furthermore, on evaluation in xenopus oocytes,(22) 29 was discovered to be a weak to moderate inverse agonist at all four receptor subtypes (alpha1, -7%; alpha2, -5%; alpha3, -16%; alpha5, -5%). Replacement of the 3-phenyl group of 29 with alternatives led to reduced affinity, and smaller 3-substituents led to reduced efficacy. Methyl substitution of the benzo-fused ring of 29 at the 7-, 8-, and 10-positions resulted in increased efficacy although selectivity was abolished. Increased efficacy and retention of selectivity for alpha3 over alpha1 was achieved with the 7,8,9,10-tetrahydro-(7,10-ethano)-phthalazine 62. Compound 62 is currently one of the most binding selective GABA-A alpha3-benzodiazepine-site partial agonists known, and although its selectivity is limited, its good pharmacokinetic profile in the rat (33% oral bioavailability after a 3 mg/kg dose, reaching a peak plasma concentration of 179 ng/mL; half-life of I h) made it a useful pharmacological tool to explore the effect of a GABA-A alpha2/alpha3 agonist in vivo.
引用
收藏
页码:1807 / 1822
页数:16
相关论文
共 40 条
  • [1] Synthesis and biological evaluation of 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimdin-5(6H)-ones as functionally selective ligands of the benzodiazepine receptor site on the GABAA receptor
    Albaugh, PA
    Marshall, L
    Gregory, J
    White, G
    Hutchison, A
    Ross, PC
    Gallagher, DW
    Tallman, JF
    Crago, M
    Cassella, JV
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (23) : 5043 - 5051
  • [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] BALASUBRAHMANYAM SN, 1978, P INDIAN ACAD SCI A, V87, P371
  • [4] Barnard EA, 1998, PHARMACOL REV, V50, P291
  • [5] 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
  • [6] PHOTOALKYLATION OF S-TRIAZOLO[4,3-B]PYRIDAZINE WITH ALCOHOLS AND GLYCOLS
    BOWN, DH
    BRADSHAW, JS
    [J]. JOURNAL OF ORGANIC CHEMISTRY, 1980, 45 (12) : 2320 - 2324
  • [7] BROUGHTON HB, 2001, Patent No. 6255305
  • [8] BUTULA I, 1979, CROAT CHEM ACTA, V52, P43
  • [9] 6,7-Dihydro-2-benzothiophen-4(5H)-ones:: A novel class of GABA-A α5 receptor inverse agonists
    Chambers, MS
    Atack, JR
    Bromidge, FA
    Broughton, HB
    Cook, S
    Dawson, GR
    Hobbs, SC
    Maubach, KA
    Reeve, AJ
    Seabrook, GR
    Wafford, K
    MacLeod, AM
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (06) : 1176 - 1179
  • [10] GABA-activated ligand gated ion channels: Medicinal chemistry and molecular biology
    Chebib, M
    Johnston, GAR
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (08) : 1427 - 1447