Biarylpyrazolyl Oxadiazole as Potent, Selective, Orally Bioavailable Cannabinoid-1 Receptor Antagonists for the Treatment of Obesity

Lee, Suk Ho; Seo, Hee Jeong; Lee, Sung-Han; Jung, Myung Eun; Park, Jihyun; Park, Hyun-Ju; Yoo, Jakyung; Yun, Hoseop; Na, Jooran; Kang, Suk Youn; Song, Kwon‐Ho; Kim, Minah; Chang, Chong-Hwan; Kim, Jeongmin; Lee, Jinhwa

doi:10.1021/jm800843r

Cited by 56 publications

(23 citation statements)

References 35 publications

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“…5) [72]. The results show that various functional groups, such as hydroxyl (22d), fluoro, vinyl, carbamate, ether, acetate, ethanethiolate, and nitrile (22c) do not block binding to the CB 1 receptor.…”

Section: Pyrazolesmentioning

confidence: 96%

“…In a manner similar to members of the 1,2,4-oxadiazole series described above, substances with an alkyl linker containing a strong electron-withdrawing group (e.g., (trifluoromethyl)cyclopropyl as in 16, IC 50 = 8.53 nM) and a sterically demanding bulky group (e.g., t-butyl as in 17, IC 50 = 7.59 nM) were found to exhibit good CB 1 R antagonism activities and selectivities [72].…”

Section: Pyrazolesmentioning

confidence: 99%

“…Green Cross Corporation scientists also described 1,5-diarylpyrazole analogs that contain a triazole-methyl group at the 4-position and an 3-oxadiazole moiety as carboxamide bioisostere [72] (23 in Fig. 16), Lilly workers prepared pyrrolidinones (e.g.…”

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

confidence: 99%

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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: Pyrazolesmentioning

confidence: 96%

Section: Pyrazolesmentioning

confidence: 99%

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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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“…Novel biarylpyrazolyl oxadiazole analogs were recently identified as orally bioavailable CB1 receptor selective antagonists for the treatment of obesity by the Green Cross [12]. In these analogs, the amide moiety in rimonabant (1) is replaced with a 1,3,4-oxadiazole as a H-bond acceptor.…”

Section: Cb1 Antagonistsmentioning

confidence: 99%

New Trends in Medicinal Chemistry Approaches to Antiobesity Therapy

Lee¹,

Song²,

Kang³

et al. 2009

CTMC

Self Cite

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The prevalences of overweightedness and obesity are increasing globally at frightening rates, driven by social and economic changes. Furthermore, obesity is associated with the pathogeneses of major diseases, particularly diabetes and cardiovascular diseases. However, no satisfactorily safe, effective obesity drugs are commercially available at the present time. Only two drugs have been approved in the United States for the long-term treatment of obesity, sibutramine and orlistat. However, these drugs are minimally effective and have significant side effects, which are likely inhibit their use. Therefore, there is a huge opportunity to make a significant impact on the lives of obese people through the discovery and development of additional pharmacotherapeutic options. In this review article, the authors focus on selected trends in medicinal chemistry and the approaches used to develop drugs for treating obesity.

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“…For the treatment of HIV, it is clear that some oxadiazol derivatives have a significant effect on diabetes, obesity (Lee, S.H., et al, 2008), inflammation (Mrityunjoy, K., et al, 2012) and anticancer (Zhang, H.Z., et al, 2005;Salem, D., et al, 2004). There are compounds containing 1, 3, 4 -oxadiazol, which are biologically effective, for example antimicrobial, antifungal, antiviral and antifungal, as well as important and useful in medical chemistry as an alternative to carboxylic acids and esters (Bostrom, J., et al, 2012) The symmetric chemistry of the complex elements of the heterogeneous cyclic compounds, including the oxadiazol legand, which have been of interest to many researchers in recent years, has been attracted by the fact that these lycandes are related to the central element ions in natural systems where the complexities exhibited significant efficacy compared to lycand (Mohmoud, N., et al, 2013;Ibrahem, S., et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 1,3,4 oxadiazol and some derivative with Cr, Zn, V, Ag

2017

Aust. J. Basic & Appl. Sci.

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Background: Heterocyclic A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements. Heterocyclic chemistry is the branch of organic chemistry dealing with the synthesis, properties, and applications of these heterocycles. Organometallic is the study of chemical compounds containing at least one chemical bond between a carbon atom of an organic compound and a metal, including alkaline, alkaline earth, transition metal, and other cases. Moreover, some related compounds such as transition metal hydrides and metal phosphine complexes are often included in discussions of organometallic compounds. The field of organometallic chemistry combines aspects of traditional inorganic and organic chemistry. Objective synthesis of Oxadiazol and some it's derivatives .Oxadiazol derivatives have been prepared with Cr , Zn , V , Ag and then theses derivatives have been diagnosed by using elemental analysis (C, H, N, S and M) and spectroscopic (IR, H 1 -NMR and UV-Visible), magnetic study and molar conductivity. Results many chemical compounds have been prepared for Oxadiazol and with some transition elements to give some important derivative compound with Oxadiazol and its entry into the treatment of many diseases. Conclusions -Oxadiazol is a center for the synthesis of many important organo metallic compounds .-The therapeutic effectiveness of the oxadiazol compounds has a strong effect for the treatment of diseases .-Oxydiazol derivatives are fixed compounds and can be used in many preparation reactions .-Physical properties measured for compounds made from oxadiazol and their derivatives show the degree of stability of these compounds chemically The compounds derived from oxadiazol with the transitional elements have a strong effect in the treatment of many diseases as well as are the center for the preparation of many pharmaceuticals .

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Biarylpyrazolyl Oxadiazole as Potent, Selective, Orally Bioavailable Cannabinoid-1 Receptor Antagonists for the Treatment of Obesity

Cited by 56 publications

References 35 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

New Trends in Medicinal Chemistry Approaches to Antiobesity Therapy

Synthesis of 1,3,4 oxadiazol and some derivative with Cr, Zn, V, Ag

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