Abstract
Since the discovery of rimonabant (Acomplia: 1), a large effort has been directed at the discovery of new, potent and selective CB1R 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 CB1R blockers for treatment of obesity ensued. However, abandoning this CB1R 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 CB1R antagonists that have been identified mainly based on modifications of the first-in-class CB1R 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 CB1R antagonists are summarized. Finally, the design of non-brain penetrating and peripherally acting CB1R antagonists, allosteric modulators of CB1R, and neutral antagonists for CB1R is also discussed in this review.
Keywords: Endocannabinoid, cannabinoid, obesity, antagonist, inverse agonist, allosteric modulator, rimonabant
Current Topics in Medicinal Chemistry
Title: The Current Status and Future Perspectives of Studies of Cannabinoid Receptor 1 Antagonists as Anti-Obesity Agents
Volume: 9 Issue: 6
Author(s): Hyeon-Kyu Lee, Eun Bok Choi and Chwang Siek Pak
Affiliation:
Keywords: Endocannabinoid, cannabinoid, obesity, antagonist, inverse agonist, allosteric modulator, rimonabant
Abstract: Since the discovery of rimonabant (Acomplia: 1), a large effort has been directed at the discovery of new, potent and selective CB1R 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 CB1R blockers for treatment of obesity ensued. However, abandoning this CB1R 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 CB1R antagonists that have been identified mainly based on modifications of the first-in-class CB1R 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 CB1R antagonists are summarized. Finally, the design of non-brain penetrating and peripherally acting CB1R antagonists, allosteric modulators of CB1R, and neutral antagonists for CB1R is also discussed in this review.
Export Options
About this article
Cite this article as:
Lee Hyeon-Kyu, Choi Bok Eun and Pak Siek Chwang, The Current Status and Future Perspectives of Studies of Cannabinoid Receptor 1 Antagonists as Anti-Obesity Agents, Current Topics in Medicinal Chemistry 2009; 9 (6) . https://dx.doi.org/10.2174/156802609788897844
DOI https://dx.doi.org/10.2174/156802609788897844 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Increased Salt Sensitivity in Obese Hypertension: Role of the Sympathetic Nervous System
Current Hypertension Reviews Systemic Therapeutic Gene Delivery for Cancer: Crafting Paris Arrow
Current Gene Therapy Antidiabetic Potential of Fabaceae Family: An Overview
Current Nutrition & Food Science Hypopituitarism in the Elderly: Multifaceted Clinical and Biochemical Presentation
Current Aging Science Angiotensin II-Vasopressin Interactions in The Regulation of Cardiovascular Functions. Evidence for an Impaired Hormonal Sympathetic Reflex in Hypertension and Congestive Heart Failure
Endocrine, Metabolic & Immune Disorders - Drug Targets Malaria Stage-Specific Vaccine Candidates
Current Pharmaceutical Design Discovery and ADMET: Where Are We Now
Current Topics in Medicinal Chemistry Biosynthetic Pathways of Bioactive N-Acylethanolamines in Brain
CNS & Neurological Disorders - Drug Targets “PARG Inhibitors’ Success: A Long Way to Go!”
Current Enzyme Inhibition Subject Index to Volume 4
Current Drug Targets - Cardiovascular & Hematological Disorders Pharmacological Interventions on Asymmetric Dimethylarginine, a Clinical Marker of Vascular Disease
Current Medicinal Chemistry Lifestyle Modification for Masked Hypertension
Current Hypertension Reviews Ischemic Colitis: Current Diagnosis and Treatment
Current Drug Targets Vasopressin Receptor Antagonists in Heart Failure
Recent Patents on Cardiovascular Drug Discovery Molecular Regulation and Pharmacology of Pacemaker Channels
Current Pharmaceutical Design Diuretics in the Treatment of Elderly Hypertensive Patients
Cardiovascular & Hematological Agents in Medicinal Chemistry Ribosome-inactivating Proteins from Root Tubers and Seeds of Trichosan-thes kirilowii and Other Trichosanthes Species
Protein & Peptide Letters Comparing the Efficacy and Safety of Dexmedetomidine/Ketamine with Propofol/Fentanyl for Sedation in Colonoscopy Patients: A Doubleblinded Randomized Clinical Trial
CNS & Neurological Disorders - Drug Targets Carbon Monoxide and the Brain: Time to Rethink the Dogma
Current Pharmaceutical Design VEGF Inhibitors in Metastatic Renal Cell Carcinoma: Current Therapies and Future Perspectives
Current Clinical Pharmacology