Constrained analogs of CB-1 antagonists: 1,5,6,7-Tetrahydro-4H-pyrrolo[3,2-c]pyridine-4-one derivatives

Smith, Roger A.; Fathi, Zahra; 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; Podlogar, Brent L.; Taing, Christy; Tomlinson, Susan A.; Tritto, Theresa; Zhang, Zhonghua

doi:10.1016/j.bmcl.2006.10.095

Cited by 26 publications

(11 citation statements)

References 22 publications

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“…Conformationally constrained tetrahydro-pyrrolopyridine-4-one analogs (D2) of rimonabant, where the carboxamide is held in a trans-conformation mimicking the X-ray structure and the calculated minimum energy and binding conformation of rimonabant, were synthesized and evaluated [Smith et al, 2007]. That the constrained conformation of D2a matches the binding conformation is supported by the comparable affinity for rimonabant (Ki 5 1.1 nM) and the lack of any major improvement in affinity.…”

Section: Conformationally Constrained Analogsmentioning

confidence: 96%

Recent CB1 cannabinoid receptor antagonists and inverse agonists

Seltzman

2009

Drug Development Research

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Antagonists or inverse agonists of the cannabinoid CB1 receptor (CB1R) reported from the 2006-2007 period are reviewed. The compounds are either variations of the archetypical cannabinoid CB1 inverse agonist rimonabant (SR141716) or are other structures less obviously related to the archetype. Many of the former class replace the core pyrazole ring of rimonabant with other ring systems to display/ arrange the appended binding/activity elements. A structure-activity relationship evolves from bioassays of these compounds that also provides a more detailed understanding of the molecular mechanism of the binding to and stabilization of the active and inactive states of the constitutively active CB1R. In addition to diverse variations of the core ring and appended substituents, conformationally constrained analogs with high affinity were revealed, a number of which do not fit a one-to-one atom correspondence with the putatively active conformations of the rimonabant template and other active analogs. Diphenylmethyl analogs were a repeated motif in structures where core rings were either absent or played less restrictive roles in structures pursuing higher conformational freedom. Bicyclic nitrogen heterocyclic ring systems as the central core structures were reported, as were linear structures including phenyl ureas and taranabant analogs. Finally, peptides in the hemopressin class were presented as CB1 antagonists. Drug Dev Res 70 : 601-615, 2009.

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Section: Conformationally Constrained Analogsmentioning

confidence: 96%

Recent CB1 cannabinoid receptor antagonists and inverse agonists

Seltzman

2009

Drug Development Research

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“…Based on the results of computational and X-ray crystallographic studies, it is believed that the preferred conformation of rimonabant (1) would have a trans-amide with the carboxamide oxygen nearly coplanar with the pyrazole ring and oriented in the same direction as the pyrazole C-4 methyl group (Fig. 13) [118,120]. Several research groups have described compounds that incorporate conformational constraints into the rimonabant (1) structure.…”

Section: Cb 1 R Antagonists Containing Constrained Bicyclic Backbonesmentioning

confidence: 98%

“…Substances in this family have the potential for increased binding affinity, resulting from an entropic advantage for the bioactive conformation, and improved pharmacokinetics due to altered resistance to metabolizing enzymes. Compounds in the series studied have a bicyclic core that effectively incorporates a constraint between the pyrazole core C-4 position and the hydrogen bond donor/ acceptor moiety [119,120].…”

Section: Cb 1 R Antagonists Containing Constrained Bicyclic Backbonesmentioning

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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“…A series of pyrrolopyridinone compounds (Table 13) have been published recently [62]. This bicyclic scaffold mimics a low energy conformation of the pyrazole 1 in which the carboxamide oxygen is oriented in the same direction as the pyrazole C-4 methyl group.…”

Section: Pyrrolopyridinonesmentioning

confidence: 98%

CB1 Cannabinoid Antagonists: Structure-Activity Relationships and Potential Therapeutic Applications

Jagerovic¹,

Fernandez-Fernandez²,

Goya

2008

CTMC

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During the last decade there has been a growing interest towards the modulation of the cannabinoid CB1 receptor. The identification of CB1 cannabinoid receptor antagonists has been one of the major advances in cannabinoid research. Thus, the development of these ligands has opened new therapeutic applications. Since the discovery of the first cannabinoid receptor antagonist, rimonabant, by Sanofi in 1994, a large number of structural variations within this chemical series of 1,5-diarylpyrazoles have been described. So far, all attempts to identify novel structures for CB1 antagonists have been based on one or more pharmacophoric elements of the rimonabant structure. The advanced clinical trials of rimonabant confirm the therapeutic potential value of CB1 antagonists for the treatment of obesity. In addition, the results of pharmacological and clinical studies reveal other effective pharmacotherapeutic applications. The current review will mainly focus on the structure-activity relationships that have been established for antagonists/inverse agonists that bind to the CB1 cannabinoid receptors and on their therapeutic applications.

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Constrained analogs of CB-1 antagonists: 1,5,6,7-Tetrahydro-4H-pyrrolo[3,2-c]pyridine-4-one derivatives

Cited by 26 publications

References 22 publications

Recent CB1 cannabinoid receptor antagonists and inverse agonists

Recent CB1 cannabinoid receptor antagonists and inverse agonists

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

CB1 Cannabinoid Antagonists: Structure-Activity Relationships and Potential Therapeutic Applications

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