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

[21] A practical, Nenitzescu-based synthesis of LY311727, the first potent and selective s-PLA(2) inhibitor [J].

Pawlak, JM ;

Khau, VV ;

Hutchison, DR ;

Martinelli, MJ .

JOURNAL OF ORGANIC CHEMISTRY, 1996, 61 (25) :9055-9059

[22] The chronobiotic properties of melatonin [J].

Pévet, P ;

Bothorel, B ;

Slotten, H ;

Saboureau, M .

CELL AND TISSUE RESEARCH, 2002, 309 (01) :183-191

[23] PINEAL MELATONIN - CELL BIOLOGY OF ITS SYNTHESIS AND OF ITS PHYSIOLOGICAL INTERACTIONS [J].

REITER, RJ .

ENDOCRINE REVIEWS, 1991, 12 (02) :151-180

[24] Melatonin receptors step into the light: Cloning and classification of subtypes [J].

Reppert, SM ;

Weaver, DR ;

Godson, C .

TRENDS IN PHARMACOLOGICAL SCIENCES, 1996, 17 (03) :100-102

[25] Melatonin, sleep, and circadian rhythms [J].

Scheer, FA ;

Czeisler, CA .

SLEEP MEDICINE REVIEWS, 2005, 9 (01) :5-9

[26] SAR by MS: Discovery of a new class of RNA-binding small molecules for the hepatitis C virus: Internal ribosome entry site IIA subdomain [J].

Seth, PP ;

Miyaji, A ;

Jefferson, EA ;

Sannes-Lowery, KA ;

Osgood, SA ;

Propp, SS ;

Ranken, R ;

Massire, C ;

Sampath, R ;

Ecker, DJ ;

Swayze, EE ;

Griffey, RH .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (23) :7099-7102

[27] Furopyridines .24. Nitration, chlorination, acetoxylation and cyanation of 2,3-dihydrofuro[2,3-b]-, -[3,2-b]-, -[2,3-c]- and -[3,2-c]pyridine N-oxides [J].

Shiotani, S ;

Kurosaki, M ;

Taniguchi, K ;

Moriyama, M .

JOURNAL OF HETEROCYCLIC CHEMISTRY, 1997, 34 (03) :941-952

[28] Melatonin in Alzheimer's disease and other neurodegenerative disorders [J].

Srinivasan V. ;

Pandi-Perumal S.R. ;

Cardinali D.P. ;

Poeggeler B. ;

Hardeland R. .

Behavioral and Brain Functions, 2 (1)

[29] Synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists [J].

Uchikawa, O ;

Fukatsu, K ;

Tokunoh, R ;

Kawada, M ;

Matsumoto, K ;

Imai, Y ;

Hinuma, S ;

Kato, K ;

Nishikawa, H ;

Hirai, K ;

Miyamoto, M ;

Ohkawa, S .

JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (19) :4222-4239

[30] Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety Attributes [J].

Wager, Travis T. ;

Chandrasekaran, Ramalakshmi Y. ;

Hou, Xinjun ;

Troutman, Matthew D. ;

Verhoest, Patrick R. ;

Villalobos, Anabella ;

Will, Yvonne .

ACS CHEMICAL NEUROSCIENCE, 2010, 1 (06) :420-434

← 1 2 3 4 →