Synthesis of a Novel Series of Tricyclic Dihydrofuran Derivatives: Discovery of 8,9-Dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridines as Melatonin Receptor (MT1/MT2) Ligands

被引：58

作者：

Koike, Tatsuki ^{[1
]}

Takai, Takafumi ^{[1
]}

Hoashi, Yasutaka ^{[1
]}

Nakayama, Masaharu ^{[1
]}

Kosugi, Yohei ^{[1
]}

Nakashima, Masato ^{[1
]}

Yoshikubo, Shin-ichi ^{[1
]}

Hirai, Keisuke ^{[1
]}

Uchikawa, Osamu ^{[1
]}

机构：

[1] Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Yodogawa Ku, Osaka 5328686, Japan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 12期

关键词：

RAMELTEON TAK-375; CIRCADIAN-RHYTHMS; AGONISTS; SLEEP; DRUG; METAANALYSIS; ANTAGONISTS; POTENT;

D O I：

10.1021/jm200385u

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Novel tricyclic dihydrofuran derivatives were designed, synthesized, and evaluated as melatonin receptor (MT1/MT2) ligands based on the previously reported 1,6-dihydro-2H-indeno[5,4-b]furan la. By screening the central tricyclic cores, we identified 8,9-dihydrofuro [3,2-c]pyrazolo [1,5-a]pyridine as a potent scaffold with a high ligand-lipophilicity efficiency (LLE) value. Subsequent optimization of the side chains led to identification of the potent MT1/MT2 agonist 4d (MT1, K-i = 0.062 nM; MT2, K-i = 0.420 nM) with good oral absorption and blood-brain barrier (BBB) penetration in rats. The oral administration of compound 4d exhibited a sleep-promoting action in freely moving cats at 0.1 mg/kg.

引用

页码：4207 / 4218

页数：12

共 32 条

[11] 1,6-Dihydro-2H-indeno[5,4-b]furan Derivatives: Design, Synthesis, and Pharmacological Characterization of a Novel Class of Highly Potent MT2-Selective Agonists
Koike, Tatsuki
Hoashi, Yasutaka
Takai, Takafumi
Nakayama, Masaharu
Yukuhiro, Nobuhito
Ishikawa, Takashi
Hirai, Keisuke
Uchikawa, Osamu
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (09) : 3436 - 3444
[12] The influence of drug-like concepts on decision-making in medicinal chemistry
Leeson, Paul D.
Springthorpe, Brian
[J]. NATURE REVIEWS DRUG DISCOVERY, 2007, 6 (11) : 881 - 890
[13] Highly efficient synthesis of O-(2,4-dinitrophenyl)hydroxylamine.: Application to the synthesis of substituted N-benzoyliminopyridinium ylides
Legault, C
Charette, AB
[J]. JOURNAL OF ORGANIC CHEMISTRY, 2003, 68 (18) : 7119 - 7122
[14] Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock
Liu, C
Weaver, DR
Jin, XW
Shearman, LP
Pieschl, RL
Gribkoff, VK
Reppert, SM
[J]. NEURON, 1997, 19 (01) : 91 - 102
[15] Systematic review and meta-analysis of the efficacy of melatonin in experimental stroke
Macleod, MR
O'Collins, T
Horky, LL
Howells, DW
Donnan, GA
[J]. JOURNAL OF PINEAL RESEARCH, 2005, 38 (01) : 35 - 41
[16] Effect of exogenous melatonin on sleep and motor dysfunction in Parkinson's disease - A randomized, double blind, placebo-controlled study
Mendes Medeiros, Camila Andrade
Carvalhedo de Bruin, Pedro Felipe
Lopes, Livia Ariane
Magalhaes, Maria Cecilia
de Lourdes Seabra, Maria
Sales de Bruin, Veralice Meireles
[J]. JOURNAL OF NEUROLOGY, 2007, 254 (04) : 459 - 464
[17] Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis
Mills, E
Wu, P
Seely, D
Guyatt, G
[J]. JOURNAL OF PINEAL RESEARCH, 2005, 39 (04) : 360 - 366
[18] The sleep-promoting action of ramelteon (TAK-375) in freely moving cats
Miyamoto, M
Nishikawa, H
Doken, Y
Hirai, K
Uchikawa, O
Ohkawa, S
[J]. SLEEP, 2004, 27 (07) : 1319 - 1325
[19] Pharmacology of Ramelteon, a Selective MT1/MT2 Receptor Agonist: A Novel Therapeutic Drug for Sleep Disorders
Miyamoto, Masaomi
[J]. CNS NEUROSCIENCE & THERAPEUTICS, 2009, 15 (01) : 32 - 51
[20] Recent advances in the development of melatonin MT1 and MT2 receptor agonists
Mor, Marco
Rivara, Silvia
Pala, Daniele
Bedini, Annalida
Spadoni, Gilberto
Tarzia, Giorgio
[J]. EXPERT OPINION ON THERAPEUTIC PATENTS, 2010, 20 (08) : 1059 - 1077

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