Discovery of pyrazine carboxamide CB1 antagonists: The introduction of a hydroxyl group improves the pharmaceutical properties and in vivo efficacy of the series

Ellsworth, Bruce A.; Wang, Ying; Zhu, Yeheng; Pendri, Annapurna; Gerritz, Samuel W.; Sun, Chuanyu; Carlson, Kenneth E.; Kang, Liya; Baska, Rose A.; Yang, Yifan; Huang, Qi; Burford, Neil T.; Cullen, Mary Jane; Johnghar, Susan; Behnia, Kamelia; Pelleymounter, Mary Ann; Washburn, William N.; Ewing, William R.

doi:10.1016/j.bmcl.2007.04.087

Cited by 35 publications

(26 citation statements)

References 31 publications

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“…Scientists at Bayer [80] and BMS [106] independently discovered that incorporation of a hydroxyl moiety on the amide side chain, as shown in 1,2-diarylimidazole-4-carboxamide 28 (Fig. 6) and 5,6-diarylpyrazine-2-carboxamide 68 (Fig.…”

Section: Efforts To Reduce the Lipophilicity And Improve The Water Somentioning

confidence: 97%

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The Current Status and Future Perspectives of Studies of Cannabinoid Receptor 1 Antagonists as Anti-Obesity Agents

Lee¹,

Choi²,

Pak³

2009

CTMC

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Since the discovery of rimonabant (Acomplia: 1), a large effort has been directed at the discovery of new, potent and selective CB(1)R antagonists that serve as anti obesity drugs. As a result, a number of compounds reached various stages of clinical trials by late 2008. However, the announcement by Sanofi-Aventis that they were discontinuing all ongoing trials with rimonabant, as a result of the finding that risks associated with depression and anxiety outweighed its benefits, had a major impact on this area. A wave of terminations of programs targeting the development of CB(1)R blockers for treatment of obesity ensued. However, abandoning this CB(1)R therapeutic target for anti-obesity drug development seems to be premature, since there are a number of potential approaches have been uncovered to circumvent the problems of the current agents. In this review, we summarize advances that have been made and the status of studies of a diverse array of CB(1)R antagonists that have been identified mainly based on modifications of the first-in-class CB(1)R antagonist, rimonabant. Various approaches have been employed to design these analogs, such as bioisosteric replacement, introduction of conformational constraints, scaffold hopping and ligand-based molecular modeling. In addition, current approaches that have been uncovered to avoid psychiatric side effects of CB(1)R antagonists are summarized. Finally, the design of non-brain penetrating and peripherally acting CB(1)R antagonists, allosteric modulators of CB(1)R, and neutral antagonists for CB(1)R is also discussed in this review.

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Section: Efforts To Reduce the Lipophilicity And Improve The Water Somentioning

confidence: 97%

“…11) [106]. Structure-activity relationship studies of a series of pyrazine carboxamides showed that pharmaceutical properties are improved by inclusion of a hydroxyl-containing side chain.…”

Section: Benzenes Pyridines and Pyrazinesmentioning

confidence: 98%

The Current Status and Future Perspectives of Studies of Cannabinoid Receptor 1 Antagonists as Anti-Obesity Agents

Lee¹,

Choi²,

Pak³

2009

CTMC

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“…The complexation of transition metal ions such as Cu (II) with pyrazolone derivatives causes them to be used as active agents in biological, pharmacological and clinical . Also, metal complexes of pyrazine have many important applications, such as electroluminescent materials, organic semiconductors, biological, pharmaceuticals and phytosanitary . Nowadays researchers use a variety of methods to synthesize inorganic complexes such as electrochemical, hydrothermal, solvothermal, microwave irradiation and ultrasound irradiation.…”

Section: Introductionmentioning

confidence: 99%

Ultrasonic‐assisted synthesis of supramolecular copper (II) complex a precursor for the preparation of octahedron Cu₂O nanoparticles applicable in the adsorption and photodegradation of Rhodamine B

Razmara

Poorsargol

2019

Applied Organom Chemis

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A copper (II) supramolecular coordination complex formulated as [Cu2(μ‐ox)2(pyz)3]n (1), (pyz = pyrazine and ox = oxalate) has been synthesized under ultrasound irradiation. 1 was characterized using various techniques such as elemental analyses, Fourier‐transform infrared spectroscopy (FT‐IR), ultraviolet–visible spectroscopy (UV–Vis), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and single crystal X‐ray diffraction (SC‐XRD). A detailed magnetic characterization of complex 1 has been carried by vibrating sample magnetometer (VSM). The M‐H hysteresis loop of 1 revealed a weak ferromagnetic behavior with the highest magnetization of 0.0123 emu/g at room temperature. Compound 1 was used as an inorganic precursor to prepare Cu2O nanoparticles through thermal decomposition at 600 °C. The obtained Cu2O has been characterized using Fourier transform infrared spectroscopy (FT‐IR), X‐ray powder diffraction (XRPD) and scanning electron microscopy (SEM). The results of SEM showed octahedron Cu2O nanoparticles with the edge lengths from 5–80 nm. Also, the adsorption ability and the photocatalytic activity of octahedral Cu2O nanoparticles in the removal of rhodamine B (RB) have been investigated. The results showed that the obtained octahedral Cu2O nanoparticles are effective in adsorption and degradation of rhodamine B from contaminated water sources. The maximum adsorption capacity and degradation efficiency of Cu2O nanoparticles were 83.3 mg/g and 91.7%, respectively. It was also found that in comparison with the commercial Cu2O, our fabricated Cu2O nanoparticles exhibit higher catalytic activity.

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“…The central cannabinoid (CB‐1) receptors are believed to play a role in controlling food consumption that contributes to weight gain . Understanding the connectivity between CB‐1 and weight gain has important practical implications because blocking the CB‐1 receptor was thought to offer a promising therapeutic approach to treating obesity . From Bristol‐Myers Squibb Discovery Chemistry efforts for the CB‐1 program, BMS‐725519, BMS‐811064, and BMS‐812204 emerged as potent and selective CB‐1 antagonists.…”

Section: Introductionmentioning

confidence: 99%

The syntheses of isotopically labelled CB‐1 antagonists for the treatment of obesity

Tran

Maxwell

Burrell

et al. 2016

Labelled Comp Radiopharmac

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BMS-725519, BMS-811064, and BMS-812204 are potent and selective central cannabinoid receptor antagonists that have been investigated for the treatment of human obesity. To further understand their biotransformation profiles, radiolabelled and stable-labelled products were required. This paper describes the utility of [ C]1,1-carbonyldiimidazole as a radiolabelling reagent for the syntheses of carbonyl-labelled [ C]BMS-725519, [ C]BMS-811064, and [ C]BMS-812204. The syntheses of stable-labelled [ C ]BMS-725519 and [ CD CD ]BMS-812204 synthesized from of [ C ]4-chloroacetophenone and [ CD CD ]iodoethane, respectively, are also described.

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Discovery of pyrazine carboxamide CB1 antagonists: The introduction of a hydroxyl group improves the pharmaceutical properties and in vivo efficacy of the series

Cited by 35 publications

References 31 publications

The Current Status and Future Perspectives of Studies of Cannabinoid Receptor 1 Antagonists as Anti-Obesity Agents

The Current Status and Future Perspectives of Studies of Cannabinoid Receptor 1 Antagonists as Anti-Obesity Agents

Ultrasonic‐assisted synthesis of supramolecular copper (II) complex a precursor for the preparation of octahedron Cu₂O nanoparticles applicable in the adsorption and photodegradation of Rhodamine B

The syntheses of isotopically labelled CB‐1 antagonists for the treatment of obesity

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Discovery of pyrazine carboxamide CB1 antagonists: The introduction of a hydroxyl group improves the pharmaceutical properties and in vivo efficacy of the series

Cited by 35 publications

References 31 publications

The Current Status and Future Perspectives of Studies of Cannabinoid Receptor 1 Antagonists as Anti-Obesity Agents

The Current Status and Future Perspectives of Studies of Cannabinoid Receptor 1 Antagonists as Anti-Obesity Agents

Ultrasonic‐assisted synthesis of supramolecular copper (II) complex a precursor for the preparation of octahedron Cu2O nanoparticles applicable in the adsorption and photodegradation of Rhodamine B

The syntheses of isotopically labelled CB‐1 antagonists for the treatment of obesity

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Ultrasonic‐assisted synthesis of supramolecular copper (II) complex a precursor for the preparation of octahedron Cu₂O nanoparticles applicable in the adsorption and photodegradation of Rhodamine B