Discovery of 4-(dimethylamino)quinazolines as potent and selective antagonists for the melanin-concentrating hormone receptor 1

Kanuma, Kosuke; Omodera, Katsunori; Nishiguchi, Mariko; Funakoshi, Takeo; Chaki, Shigeyuki; Semple, Graeme; Tran, Thuy-Anh; Kramer, Bryan; Hsu, Debbie; Casper, Martin D.; Thomsen, Bill; Beeley, N. R. A.; Sekiguchi, Yoshinori

doi:10.1016/j.bmcl.2005.03.052

Cited by 25 publications

(4 citation statements)

References 9 publications

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“…The reaction of 2‐chloroquinazoline [30] ( 33 , 2.0 g, 12 mmol) with 3‐furyllithium (12.5 mmol) and aromatization of the intermediate dihydroquinazoline by treatment with DDQ was conducted by using the general procedure described earlier. A mixture of the resultant crude product 34 , N ‐methylpiperazine 3 mL, 3 mmol, and toluene 15 mL was heated under reflux for 3 h, and the final product 35 was isolated and purified as described earlier.…”

Section: Methodsmentioning

confidence: 99%

“…2‐Chloroquinazoline [30] (2.75 g, 12 mmol) in tetrahydrofuran (30 mL) was allowed to react with vinyllithium (12.5 mmol), and then the mixture was quenched by using the general procedure described earlier. A mixture of crude 2‐chloro‐4‐vinyl‐3,4‐dihydroquinazoline thus obtained, potassium hydroxide (40 mg, 0.7 mmol), potassium ferricyanide (0.18 g, 0.55 mmol), water (0.3 mL), and benzene (1.5 mL) were stirred at 23 ° C for 5 h, and then treated with benzene (15 ml) and water (15 ml).…”

Section: Methodsmentioning

confidence: 99%

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Synthesis of 4‐substituted 2‐(4‐methylpiperazino)pyrimidines and quinazoline analogs as serotonin 5‐HT_2A receptor ligands

Sączewski

Paluchowska

Klenc

et al. 2009

Journal of Heterocyclic Chem

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in Wiley InterScience (www.interscience.wiley.com).The addition reaction of lithium reagents to the 4 position of 2-chloropyrimidine or 2-chloroquinazoline followed by oxidation of the resultant dihydro intermediate product is a powerful tool for the synthesis of 4-substituted 2-chloropyrimidines or 2-chloroquinazolines. 4-Vinyl derivatives undergo a conjugate nucleophilic addition across the vinyl group. A nucleophilic displacement of chloride in 4-substituted 2-chloropyrimidines or 2-chloroquinazolines by treatment with 4-methylpiperazine provides compounds that are antagonists of the serotonin 5-HT 2A receptor.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Synthesis of 4‐substituted 2‐(4‐methylpiperazino)pyrimidines and quinazoline analogs as serotonin 5‐HT_2A receptor ligands

Sączewski

Paluchowska

Klenc

et al. 2009

Journal of Heterocyclic Chem

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“…These anxiolytic effects were not supported by another group [64]. Several other small molecule antagonists were developed from pharmaceutical companies, e.g., ATC0065 and ATC0175 (Arena/Taisho collaboration) [65,66], GW803430 (GlaxoSmithKline) [67], SNAP 94847 (Synaptic/Lundbeck) [52], AMG-076 (Amgen) [68], and NGD-4715 (Neurogen) [69]. All these drugs are BBB-penetrating compounds, which is mandatory to reduce body weight [70].…”

Section: Targeting the Mchr1mentioning

confidence: 99%

The Potential Role of the MCHR1 in Diagnostic Imaging: Facts and Trends

Philippe¹,

Mitterhauser²

2017

Melanin

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The neuropeptide melanin-concentrating hormone (MCH) plays a key role in energy maintenance by decreasing energy expenditure and stimulating feeding behavior. Furthermore, it is involved in diabetes, gut inflammation, sleep, depression, and cilia beat function. The biological function of MCH is mediated by two G-protein coupled receptors, MCH receptor 1 and 2 (MCHR1 and MCHR2). Since only the MCHR1 is functional in rodents, the physiological importance of MCHR2 remains unknown due to the lack of appropriate animal models. The involvement of the MCHergic system in a variety of pathologies, especially endocrinological diseases, such as obesity and diabetes, makes it interesting as a new target to treat human disorders. Many pharmaceutical companies have pursued the development of MCHR1 antagonists for the treatment of obesity. Moreover, positron emission tomography (PET) tracers targeting the MCHR1 have been developed in order to gain a deeper understanding of the role and distribution of the MCHR1. As a high-end technique, PET allows noninvasive in vivo visualization and quantification of receptor systems, as well as monitoring and following hormone receptor status and related pathologies. Therefore, a MCHR1 PET tracer could help to guide pharmacological intervention via the MCHR1.

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“…3e). High throughput screening of the GPCR directed library uncovered a series of 4-(dimethylamino) quinazolines as MCH1R antagonists [Kanuma et al, 2005a]. Through the SAR investigation, we identified a new class of potent and selective nonpeptidic antagonists for MCH1R, exemplified by ATC0065 (8, IC 50 5 16 nM) and ATC0175 (9, IC 50 5 7.2 nM) [Chaki et al, 2005;Kanuma et al, 2005aKanuma et al, , 2005b.…”

Section: Nonpeptidic Mch1r Antagonistsmentioning

confidence: 99%

Melanin‐concentrating hormone receptor 1 antagonists for the treatment of depression and anxiety

Chaki

Yamaguchi

Yamada

et al. 2005

Drug Development Research

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Melanin-concentrating hormone (MCH) is a cyclic, 19-amino-acid neuropeptide produced in the lateral hypothalamus. MCH is implicated in a number of physiological processes including feeding behavior, energy balance, reproductive function, memory, sleep-wake regulation, and emotional states. Since the discoveries in the mid-1990 s that MCH is an appetite stimulant in rodents and that KO mice lacking MCH become lean, together with the findings that MCH receptor 1 (MCH1R) is responsible for these functions, most research has been focused on the roles of the MCH system in feeding and energy homeostasis. It is now established that MCH plays a key role in controlling feeding and energy homeostasis via MCH1R, and some pharmaceutical companies have reported nonpeptidic MCH1R antagonists with diverse structural features in the treatment of obesity. Recently, emerging lines of evidence have indicated that MCH1R plays important roles not only in feeding and energy balance but also in regulation of emotion. Indeed, MCH1R is widely distributed in the regions associated with emotion, and MCH1R antagonists have been demonstrated to exhibit antidepressant and anxiolytic effects in various rodent models. This review describes recent advances in research to clarify the involvement of MCH in depression and anxiety. The paper will also discuss the potential value of MCH1R antagonists in the treatment of depressive and anxiety disorders. Drug Dev. Res. 65:278-290, 2005.

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Discovery of 4-(dimethylamino)quinazolines as potent and selective antagonists for the melanin-concentrating hormone receptor 1

Cited by 25 publications

References 9 publications

Synthesis of 4‐substituted 2‐(4‐methylpiperazino)pyrimidines and quinazoline analogs as serotonin 5‐HT_2A receptor ligands

Synthesis of 4‐substituted 2‐(4‐methylpiperazino)pyrimidines and quinazoline analogs as serotonin 5‐HT_2A receptor ligands

The Potential Role of the MCHR1 in Diagnostic Imaging: Facts and Trends

Melanin‐concentrating hormone receptor 1 antagonists for the treatment of depression and anxiety

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Discovery of 4-(dimethylamino)quinazolines as potent and selective antagonists for the melanin-concentrating hormone receptor 1

Cited by 25 publications

References 9 publications

Synthesis of 4‐substituted 2‐(4‐methylpiperazino)pyrimidines and quinazoline analogs as serotonin 5‐HT2A receptor ligands

Synthesis of 4‐substituted 2‐(4‐methylpiperazino)pyrimidines and quinazoline analogs as serotonin 5‐HT2A receptor ligands

The Potential Role of the MCHR1 in Diagnostic Imaging: Facts and Trends

Melanin‐concentrating hormone receptor 1 antagonists for the treatment of depression and anxiety

Contact Info

Product

Resources

About

Synthesis of 4‐substituted 2‐(4‐methylpiperazino)pyrimidines and quinazoline analogs as serotonin 5‐HT_2A receptor ligands

Synthesis of 4‐substituted 2‐(4‐methylpiperazino)pyrimidines and quinazoline analogs as serotonin 5‐HT_2A receptor ligands