Tetrazole-biarylpyrazole derivatives as cannabinoid CB1 receptor antagonists

Kang, Suk Youn; Lee, Sung-Han; Seo, Hee Jeong; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Jeongmin; Lee, Jinhwa

doi:10.1016/j.bmcl.2008.02.061

Cited by 36 publications

(7 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The tetrazole motif is an important synthetic scaffold that found broad applications in numerous fields such as in medicine, biochemistry, pharmacology, and in industry as materials, e.g., in photography, imaging chemicals, and military. − Indicatively, tetrazole derivatives are investigated both as a potential explosives and as rocket propellant components based on their high energy properties. − Moreover, tetrazoles, due to their high number of nitrogen atoms, could serve as an environmentally benign component of gas generators with a high burn rate and relative stability . However, the most important and fruitful application of tetrazoles with many future prospects is their utility in medicinal chemistry. − Not surprisingly, the number of publications on new drugs and promising biologically active compounds containing the tetrazole moiety increased dramatically the last seven years, 2010–2017 (Scopus, SciFinder, Figure ).…”

Section: Introductionmentioning

confidence: 99%

Tetrazoles via Multicomponent Reactions

2019

View full text Add to dashboard Cite

Tetrazole derivatives are a prime class of heterocycles, very important to medicinal chemistry and drug design due to not only their bioisosterism to carboxylic acid and amide moieties but also to their metabolic stability and other beneficial physicochemical properties. Although more than 20 FDA-approved drugs contain 1H- or 2H-tetrazole substituents, their exact binding mode, structural biology, 3D conformations, and in general their chemical behavior is not fully understood. Importantly, multicomponent reaction (MCR) chemistry offers convergent access to multiple tetrazole scaffolds providing the three important elements of novelty, diversity, and complexity, yet MCR pathways to tetrazoles are far from completely explored. Here, we review the use of multicomponent reactions for the preparation of substituted tetrazole derivatives. We highlight specific applications and general trends holding therein and discuss synthetic approaches and their value by analyzing scope and limitations, and also enlighten their receptor binding mode. Finally, we estimated the prospects of further research in this field.

show abstract

Section: Introductionmentioning

confidence: 99%

Tetrazoles via Multicomponent Reactions

2019

View full text Add to dashboard Cite

show abstract

“…These substances display moderate activities towards CB 1 receptors. The cyclopentyl-tetrazole-biarylpyrazole 18 exhibits a high activity as well as good selectivity for CB 1 R over CB 2 R (IC 50 = 11.6 nM, CB 1 /CB 2 = 366) [73].…”

Section: Pyrazolesmentioning

confidence: 99%

“…3-Tetrazole-biarylpyrazole 18 [73], 3-imidazole-biarylpyrazole 19 [74], biarylpyrazole containing amino alcohol moieties at the C3-position, and 3-morpholinyl-biarylpyrazole derivatives 20 and 21 [75] serve as viable bioisosteric replacements of the 3-carboxamide of rimonabant. These substances display moderate activities towards CB 1 receptors.…”

Section: Pyrazolesmentioning

confidence: 99%

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

Lee¹,

Choi²,

Pak³

2009

CTMC

View full text Add to dashboard Cite

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.

show abstract

“…Among many heterocycles involving this particular type of functionality, they initially focused their attention on tetrazole as a viable amide surrogate, since modification of the amide moiety into tetrazole could impart a favorable balance of potency and physicochemical properties to allow for further in vivo evaluation [40]. Among many heterocycles involving this particular type of functionality, they initially focused their attention on tetrazole as a viable amide surrogate, since modification of the amide moiety into tetrazole could impart a favorable balance of potency and physicochemical properties to allow for further in vivo evaluation [40].…”

Section: Tetrazole As Amide Bioisosterementioning

confidence: 99%

The Bioisosteric Concept Applied to Cannabinoid Ligands

Mugnaini

Pasquini²,

Corelli³

2012

CMC

View full text Add to dashboard Cite

Bioisosterism is widely used in medicinal chemistry as an approach aimed at either rationally modifying a hit compound into a more potent and/or selective molecule or a lead compound into a more drug-like one. Two different cannabinoid receptors have been cloned from mammalian tissues, the CB1 receptor, mostly expressed in brain, and the CB2 receptor, mostly expressed in the immune system, both regulating a variety of physiological functions. Synthetic cannabinoids have been developed that act as highly selective agonists or antagonists/inverse agonists at one or other of these receptor types with the ultimate goal of modulating the endocannabinoid system. This review takes into account the use of the bioisosteric substitution in the field of cannabinoid ligands as a tool for improving both their pharmacodynamic and pharmacokinetic properties.

show abstract

Tetrazole-biarylpyrazole derivatives as cannabinoid CB1 receptor antagonists

Cited by 36 publications

References 21 publications

Tetrazoles via Multicomponent Reactions

Tetrazoles via Multicomponent Reactions

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

The Bioisosteric Concept Applied to Cannabinoid Ligands

Contact Info

Product

Resources

About