Synthesis and Structure–Activity Relationships of Pyrazolo[1,5-<i>a</i>]pyridine Derivatives: Potent and Orally Active Antagonists of Corticotropin-Releasing Factor 1 Receptor

Takahashi, Yūzō; Hibi, Shigeki; Hoshino, Yorihisa; Kikuchi, Koichi; Shin, Kogyoku; Murata-Tai, Kaoru; Fujisawa, Masae; Ino, Mitsuhiro; Shibata, Hajime; Yonaga, Masahiro

doi:10.1021/jm300259r

Cited by 36 publications

(22 citation statements)

References 33 publications

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“…Here, we compared the effect of E2508 and diazepam on spontaneous locomotor activity in mice. As described above, E2508 shows significant anxiolytic effects in the light/dark test in BALB/c mice at 10 mg/kg [16].…”

Section: Effect Of E2508 and Diazepam On Spontaneous Locomotor Activimentioning

confidence: 62%

“…We previously reported that E2508 has a high affinity for the human (h) CRF1 receptor, with Ki values of 11.3 nM and >10 M for the hCRF1 and hCRF2 receptors, respectively [16]. In comparison, the reference compound, R121919, had a Ki value of 8.3 nM for the hCRF1 receptor.…”

Section: Inhibitory Effect Of E2508 and R121919 On Crf-induced Camp Pmentioning

confidence: 98%

“…The anxiolytic-like effect of E2508 was compared with the reference compounds, R121919 and diazepam. Orally We previously examined the anxiolytic-like effect of E2508 using a conventional light/dark test in mice [16], finding that E2508 significantly increased both time spent in the light box and the number of crosses at 10 mg/kg in BALB/c mice. Taken together, the results from our two studies demonstrate that E2508 has a robust anxiolytic-like effect in rodent models, and appears to be markedly more potent than diazepam in the defensive burying test.…”

Section: Effect Of E2508 R121919 and Diazepam On The Defensive Burymentioning

confidence: 99%

“…In the first clinical phase IIa study, the CRF1 receptor antagonist, receptor antagonist with a pyrazolo[1,5-a]pyridine core ( Fig. 1) [16]. The compound potently binds to the human CRF1 receptor in vitro and displays appropriate drug-like characteristics.…”

Section: Introductionmentioning

confidence: 99%

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Selective corticotropin-releasing factor 1 receptor antagonist E2508 has potent antidepressant-like and anxiolytic-like properties in rodent models

Taguchi

Shikata

Furuya

et al. 2016

Behavioural Brain Research

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Section: Effect Of E2508 and Diazepam On Spontaneous Locomotor Activimentioning

confidence: 62%

Section: Inhibitory Effect Of E2508 and R121919 On Crf-induced Camp Pmentioning

confidence: 98%

Section: Effect Of E2508 R121919 and Diazepam On The Defensive Burymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Selective corticotropin-releasing factor 1 receptor antagonist E2508 has potent antidepressant-like and anxiolytic-like properties in rodent models

Taguchi

Shikata

Furuya

et al. 2016

Behavioural Brain Research

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“…Recently, much attention has been paid to pyridine and its derivatives due to their wide applications in different fields of medicine and material chemistry, most of which have potential biological activity [2,3 ]. There are two crystallographically independant moleculesinthe asymmetric unit of the title crystal structure, in which all bond lengths are within normal ranges.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of 3,4,5-trimethoxy-N-(4-(4-methoxyphenyl)-6-phenyl pyridin-2-yl)benzamide, C56H52N4O10

Guo

Hou

2013

Zeitschrift Für Kristallographie - New Crystal Structures

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Source of materialTo asolutionof3,4,5-trimethoxybenzoic acid (1.06g,5.0 mmol) in anhydrousdichloromethane and acatalytic amount of DMF, oxalyl chloride (1.27 g, 10.0mmol) was added at room temperature. The reaction was stirred at room temperature for 3hand then evaporated under reduced pressure. The residue was triturated with dichloromethane and evaporated. The acid chloride was then dissolved in dichloromethane and added dropwise to asolution of 4-(4-methoxyphenyl)-6-phenylpyridin-2-amine (1.16 g, 4.2 mmol) ,triethylamine (1.2 ml, 8.4 mmol) and catalytic amounts of DMAP in dichloromethane at 273-278K. The reaction was monitored by TLC(thin layer chromatography), and the product wasisolated afterwashing thereactionmixture with asaturated aqueous NaCl solution, dried over anhydrous Na 2 SO 4 ,and evaporated. The residue was further purified by columnchromatography (PE/EA =8 :1) to give the title compound as ac olourless solid, m.p.: 453-454K. Yield 1.43 g, 72% [1].Finally, 10 mg of the title compound were dissolved in am ixture of PE/EA( 1:3, v/v), and the solution was kept at room temperature for five days. Naturale vaporation gave whiten eedle-shaped crystals suitable for X-ray diffraction analysis. DiscussionRecently, much attention has been paid to pyridine and its derivatives due to their wide applications in different fields of medicine and material chemistry, most of which have potential biological activity [2,3 ]. There are two crystallographically independant moleculesinthe asymmetric unit of the title crystal structure, in which all bond lengths are within normal ranges. There are three benzene rings and one pyridine ring in each molecule. In both molecules, the pyridine ring is nearly coplanar with the benzene ring containing atomsC 1t oC 6, and C29 to C34, respectively. The torsion angles of C18-N2-C17-N1, C46-N4-C45-N3, C17-N2-C18-C19 and C45-N4-C46-C47 are 170.

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Palladium‐Catalyzed Direct Arylations of 1,2‐Azolo[1,5‐a]pyridines using Copper(I) Chloride as a Lewis Acid Activator and the Synthesis of 2,6‐Disubstituted Pyridines

Kim

Lee

et al. 2015

Adv Synth Catal

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A direct method for the arylation of 1,2‐azolo[1,5‐a]pyridines has been developed. In the process, the fused pyridines react with aryl halides in the presence of the palladium complex Pd(OAc)2(Phen) as a catalyst and copper(I) chloride (CuCl) as a Lewis acid to form arylated derivatives. While pyrazolo[1,5‐a]pyridines and [1,2,4]triazolo[1,5‐a]pyridines are arylated at ortho‐positions of their pyridine rings using this method, in situ ring‐opening of the formed C‐7 arylated [1,5‐a]pyridine takes place to generate the 2,6‐disubstituted pyridine. Also, upon treatment with lithium diisopropylamide (LDA), C‐7 arylated pyrazolo[1,5‐a]pyridine‐3‐carboxylates react to produce diversely substituted 2,6‐disubstituted pyridines. Finally, a sequential C‐3 arylation was accomplished through a two‐step sequence involving hydrolysis of pyrazolo[1,5‐a]pyridine‐3‐carboxylates followed by the bimetallic Pd/Cu‐catalyzed decarboxylative coupling reaction with aryl bromide.magnified image

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Synthesis and Structure–Activity Relationships of Pyrazolo[1,5-a]pyridine Derivatives: Potent and Orally Active Antagonists of Corticotropin-Releasing Factor 1 Receptor

Cited by 36 publications

References 33 publications

Selective corticotropin-releasing factor 1 receptor antagonist E2508 has potent antidepressant-like and anxiolytic-like properties in rodent models

Selective corticotropin-releasing factor 1 receptor antagonist E2508 has potent antidepressant-like and anxiolytic-like properties in rodent models

Crystal structure of 3,4,5-trimethoxy-N-(4-(4-methoxyphenyl)-6-phenyl pyridin-2-yl)benzamide, C56H52N4O10

Palladium‐Catalyzed Direct Arylations of 1,2‐Azolo[1,5‐a]pyridines using Copper(I) Chloride as a Lewis Acid Activator and the Synthesis of 2,6‐Disubstituted Pyridines

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