Lead optimization of 4-(dimethylamino)quinazolines, 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; Sekiguchi, Yoshinori

doi:10.1016/j.bmcl.2005.05.121

Cited by 30 publications

(9 citation statements)

References 11 publications

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“…1 H NMR (500 MHz, CD 3 OD) δ 7.92 (d, J = 9.1 Hz, 1H), 7.43 (d, J = 1.0 Hz, 1H), 7.01 (dd, J = 9.1, 2.5 Hz, 1H), 6.91 (d, J = 2.3 Hz, 1H), 6.35 (s, 2H), 4.76 (s, 2H), 3.88 (s, 3H). 13 N 4 -(Furan-2-ylmethyl)-N 2 -isopropyl-7-methoxyquinazoline-2,4-diamine (27). 0.065 g (0.29 mmol) of 27d was reacted with isopropylamine according to general procedure Db to give 0.007 g (0.022 mmol) of the title compound in 8% yield.…”

Section: ■ Conclusionmentioning

confidence: 99%

Antileishmanial Activity of a Series of N²,N⁴-Disubstituted Quinazoline-2,4-diamines

et al. 2014

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A series of N2,N4-disubstituted quinazoline-2,4-diamines has been synthesized and tested against Leishmania donovani and L. amazonensis intracellular amastigotes. A structure–activity and structure–property relationship study was conducted in part using the Topliss operational scheme to identify new lead compounds. This study led to the identification of quinazolines with EC50 values in the single digit micromolar or high nanomolar range in addition to favorable physicochemical properties. Quinazoline 23 also displayed efficacy in a murine model of visceral leishmaniasis, reducing liver parasitemia by 37% when given by the intraperitoneal route at 15 mg kg–1 day–1 for 5 consecutive days. Their antileishmanial efficacy, ease of synthesis, and favorable physicochemical properties make the N2,N4-disubstituted quinazoline-2,4-diamine compound series a suitable platform for future development of antileishmanial agents.

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Section: ■ Conclusionmentioning

confidence: 99%

Antileishmanial Activity of a Series of N²,N⁴-Disubstituted Quinazoline-2,4-diamines

et al. 2014

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“…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: 98%

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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“…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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Lead optimization of 4-(dimethylamino)quinazolines, potent and selective antagonists for the melanin-concentrating hormone receptor 1

Cited by 30 publications

References 11 publications

Antileishmanial Activity of a Series of N²,N⁴-Disubstituted Quinazoline-2,4-diamines

Antileishmanial Activity of a Series of N²,N⁴-Disubstituted Quinazoline-2,4-diamines

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

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

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Lead optimization of 4-(dimethylamino)quinazolines, potent and selective antagonists for the melanin-concentrating hormone receptor 1

Cited by 30 publications

References 11 publications

Antileishmanial Activity of a Series of N2,N4-Disubstituted Quinazoline-2,4-diamines

Antileishmanial Activity of a Series of N2,N4-Disubstituted Quinazoline-2,4-diamines

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

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

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Antileishmanial Activity of a Series of N²,N⁴-Disubstituted Quinazoline-2,4-diamines

Antileishmanial Activity of a Series of N²,N⁴-Disubstituted Quinazoline-2,4-diamines