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：61

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 [J].

Koike, Tatsuki ;

Hoashi, Yasutaka ;

Takai, Takafumi ;

Nakayama, Masaharu ;

Yukuhiro, Nobuhito ;

Ishikawa, Takashi ;

Hirai, Keisuke ;

Uchikawa, Osamu .

JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (09) :3436-3444

[12] The influence of drug-like concepts on decision-making in medicinal chemistry [J].

Leeson, Paul D. ;

Springthorpe, Brian .

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 [J].

Legault, C ;

Charette, AB .

JOURNAL OF ORGANIC CHEMISTRY, 2003, 68 (18) :7119-7122

[14] Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock [J].

Liu, C ;

Weaver, DR ;

Jin, XW ;

Shearman, LP ;

Pieschl, RL ;

Gribkoff, VK ;

Reppert, SM .

NEURON, 1997, 19 (01) :91-102

[15] Systematic review and meta-analysis of the efficacy of melatonin in experimental stroke [J].

Macleod, MR ;

O'Collins, T ;

Horky, LL ;

Howells, DW ;

Donnan, GA .

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 [J].

Mendes Medeiros, Camila Andrade ;

Carvalhedo de Bruin, Pedro Felipe ;

Lopes, Livia Ariane ;

Magalhaes, Maria Cecilia ;

de Lourdes Seabra, Maria ;

Sales de Bruin, Veralice Meireles .

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 [J].

Mills, E ;

Wu, P ;

Seely, D ;

Guyatt, G .

JOURNAL OF PINEAL RESEARCH, 2005, 39 (04) :360-366

[18] The sleep-promoting action of ramelteon (TAK-375) in freely moving cats [J].

Miyamoto, M ;

Nishikawa, H ;

Doken, Y ;

Hirai, K ;

Uchikawa, O ;

Ohkawa, S .

SLEEP, 2004, 27 (07) :1319-1325

[19] Pharmacology of Ramelteon, a Selective MT1/MT2 Receptor Agonist: A Novel Therapeutic Drug for Sleep Disorders [J].

Miyamoto, Masaomi .

CNS NEUROSCIENCE & THERAPEUTICS, 2009, 15 (01) :32-51

[20] Recent advances in the development of melatonin MT1 and MT2 receptor agonists [J].

Mor, Marco ;

Rivara, Silvia ;

Pala, Daniele ;

Bedini, Annalida ;

Spadoni, Gilberto ;

Tarzia, Giorgio .

EXPERT OPINION ON THERAPEUTIC PATENTS, 2010, 20 (08) :1059-1077

← 1 2 3 4 →