Optimization of imidazole amide derivatives as cannabinoid-1 receptor antagonists for the treatment of obesity

Smith, Roger A.; Fathi, Zahra; Achebe, Furahi; Akuche, Christiana; Brown, Su-Ellen; Choi, Soongyu; Fan, Jianmei; Jenkins, Susan; Kluender, Harold C.; Konkar, Anish; Lavoie, Rico; Mays, Ronald; Natoli, Jennifer; OʼConnor, Stephen J; Ortiz, Astrid; Su, Ning; Taing, Christy; Tomlinson, Susan A.; Tritto, Theresa; Gan, Wang; Wirtz, Stephan-Nicholas; Wong, Wai C.; Yang, Xiaofan; Ying, Sheng‐Hua; Zhang, Zhonghua

doi:10.1016/j.bmcl.2007.03.011

Cited by 14 publications

(9 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[2] Substituted imidazoles are a privileged structural motif that is prevalent in pharmaceutical small molecules with diverse biological activities, including inflammation, [3] HIV, [4] depression, [5] and various other disease areas. [6] …”

mentioning

confidence: 99%

Enantioselective N‐Heterocyclic Carbene Catalyzed Annulation Reactions with Imidazolidinones

McCusker

Scheidt

2013

Angew Chem Int Ed

View full text Add to dashboard Cite

mentioning

confidence: 99%

Enantioselective N‐Heterocyclic Carbene Catalyzed Annulation Reactions with Imidazolidinones

McCusker

Scheidt

2013

Angew Chem Int Ed

View full text Add to dashboard Cite

“…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%

“…During studies aimed at optimization of the acitivities of imidazole amide derivatives, workers at Bayer discovered that incorporation of a hydroxyl group on the cyclohexyl ring of 1,2-diarylimidazole-4-carboxamides leads to a dramatic improvement in oral bioavailability [80]. Optimization of these substances provided the imidazole 2-hydroxycyclohexyl amide 28, which exhibited a hCB 1 R K i of 3.7 nM, and caused significant appetite suppression and robust, dose-dependent reduction of body weight gain in industrystandard rat models.…”

Section: Imidazolesmentioning

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

“…Tertiary imidazole-4(5)-carboxamides have found a range of applications in drug discovery, for example, as cholecystokinin 1 receptor , and cannabinoid receptor 1 agonists, as protease inhibitors, carbonic anhydrase inhibitors, potassium channel inhibitors, and as histamine H3 receptor modulators . Their precursor carboxylic acids are somewhat difficult to isolate due to their zwitterionic nature.…”

mentioning

confidence: 99%

Synthesis of Tertiary Amides from Anionically Activated Aromatic Trifluoromethyl Groups

O’Mahony

Pitts

2010

Org. Lett.

View full text Add to dashboard Cite

In this paper, a novel synthesis of tertiary amides from anionically activated aromatic trifluoromethyl groups is presented. Anionically activated trifluoromethyl groups react with secondary amines under aqueous conditions to afford tertiary amides. The mechanism involves initial elimination of hydrogen fluoride by an E1cB mechanism to afford an electrophilic quinone methide- or azafulvene-type intermediate that reacts with secondary amines under aqueous conditions to afford the tertiary amide in good yield (up to 99%).

show abstract

Optimization of imidazole amide derivatives as cannabinoid-1 receptor antagonists for the treatment of obesity

Cited by 14 publications

References 22 publications

Enantioselective N‐Heterocyclic Carbene Catalyzed Annulation Reactions with Imidazolidinones

Enantioselective N‐Heterocyclic Carbene Catalyzed Annulation Reactions with Imidazolidinones

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

Synthesis of Tertiary Amides from Anionically Activated Aromatic Trifluoromethyl Groups

Contact Info

Product

Resources

About