Discovery of 1‐(2,4‐Dichlorophenyl)‐4‐ethyl‐5‐(5‐(2‐(4‐(trifluoromethyl)phenyl)ethynyl)thiophen‐2‐yl)‐N‐(piperidin‐1‐yl)‐1H‐pyrazole‐3‐carboxamide as a Potential Peripheral Cannabinoid‐1 Receptor Inverse Agonist

@article{Hung2010DiscoveryO1,
  title={Discovery of 1‐(2,4‐Dichlorophenyl)‐4‐ethyl‐5‐(5‐(2‐(4‐(trifluoromethyl)phenyl)ethynyl)thiophen‐2‐yl)‐N‐(piperidin‐1‐yl)‐1H‐pyrazole‐3‐carboxamide as a Potential Peripheral Cannabinoid‐1 Receptor Inverse Agonist},
  author={Ming-Shiu Hung and Chun-Ping Chang and Ting‐Chieh Li and Teng Kuang Yeh and Jen-Shin Song and Yinchiu Lin and Chien-Huang Wu and Po-Chu Kuo and Prashanth Kumar Amancha and Ying-Chieh Wong and Wenchi Hsiao and Yu-sheng Chao and Kak‐Shan Shia},
  journal={ChemMedChem},
  year={2010},
  volume={5}
}
Cannabinoid-1 receptor (CB1R) is one of the most abundant neuroregulatory receptors in the brain, and it is involved in regulating feeding and appetite. In addition to expression in brain, this receptor is also found in the peripheral organs, such as adipose tissues, muscle, and liver. In sharp contrast, the structurally closely related cannabinoid-2 receptor (CB2R) is expressed almost exclusively in the immune system and is primarily involved in immune regulation and neurodegeneration. The… 
Discovery of 1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4-((pyrrolidine-1-sulfonamido)methyl)-5-(5-((4-(trifluoromethyl)phenyl)ethynyl)thiophene-2-yl)-1H-pyrazole-3-carboxamide as a novel peripherally restricted cannabinoid-1 receptor antagonist with significant weight-loss efficacy in diet-induced o
TLDR
It is found that many structurally diverse bioisosteres could be generated via derivatizing the C-4 alkyl chain on the pyrazole ring of compound 3 with different electronegative groups, leading to the identification of compound 4 (B/P = 1/64) as a peripherally restricted CB1R antagonist.
Cannabinoid receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
TLDR
There are currently three licenced cannabinoid medicines each of which contains a compound that can activate CB1 and CB2 receptors, and one of them, Sativex®, contains mainly Δ9-tetrahydrocannabinol and cannabidiol, both extracted from cannabis, and is used to treat multiple sclerosis and cancer pain.
Exploring structural requirements for peripherally acting 1,5-diaryl pyrazole-containing cannabinoid 1 receptor antagonists for the treatment of obesity
TLDR
Several novel highly selective peripherally acting CB1 receptor antagonists have been designed and reported herein using the inputs from the best CoMSIA contour maps.
4-Cyano-5-(2-thiophenyl)-pyrazoles are high affinity CB1 receptor ligands
Pyrazoles bearing a 5-thiophenyl and a 4-cyano group were synthesised and tested for their affinity to the cannabinoid CB1 receptor showing in many cases single digit nanomolar Ki values and moderate
Pyrazole antagonists of the CB1 receptor with reduced brain penetration.
TLDR
Novel analogs of rimonabant were explored in which the piperidine nitrogen was functionalized with carbamates, amides, and sulfonamides, providing compounds that are potent inverse agonists of h CB1 with good selectivity for hCB1 over hCB2.
Cannabis: From a Plant That Modulates Feeding Behaviors toward Developing Selective Inhibitors of the Peripheral Endocannabinoid System for the Treatment of Obesity and Metabolic Syndrome
TLDR
The role of the endocannabinoid (eCB) system in regulating energy and metabolic homeostasis is discussed and various novel compounds that block CB1R only in peripheral organs with very limited brain penetration and without causing behavioral side effects are developed.
Second generation CB1 receptor blockers and other inhibitors of peripheral endocannabinoid overactivity and the rationale of their use against metabolic disorders
TLDR
An overview of the roles the ECS plays outside the brain in regulating metabolism is provided, and the latest advances in the development of neutral and/or peripherally restricted CB1 antagonists, and other state of the art strategies that minimize endocannabinoid overactivity are highlighted.
Prospective therapeutic agents for obesity: molecular modification approaches of centrally and peripherally acting selective cannabinoid 1 receptor antagonists.
TLDR
It has been observed that some of the peripherally acting compounds do not show adverse effects and could be used as potential leads for the further design of selective CB1 receptor antagonists.
Peripherally restricted CB1 receptor blockers.
  • R. J. Chorvat
  • Chemistry, Medicine
    Bioorganic & medicinal chemistry letters
  • 2013
TLDR
Focus will be on the pharmacology supporting the contention that reported agents are truly peripherally restricted, and methodology that can be used to eliminate BBB penetration and the means to identify potential agents with little brain presence.
NESS06SM reduces body weight with an improved profile relative to SR141716A.
TLDR
The results suggest that NESS06SM reduces body weight and it can restore the disrupted expression profile of genes linked to the hunger-satiety circuit without altering monoaminergic transmission probably avoiding SR141716A side effects.
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References

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Bioisosteric replacement of the pyrazole 5-aryl moiety of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A). A novel series of alkynylthiophenes as potent and selective cannabinoid-1 receptor antagonists.
TLDR
A novel class of 5-(5-alkynyl-2-thienyl)pyrazole derivatives, behaving as highly potent CB1 receptor antagonists with good CB1/2 selectivity, was discovered, many of which showed significant weight reduction in diet-induced obese mouse model, thus pharmacologically validating that the bioisosteric replacement described above is viable.
CB1 receptors in the preoptic anterior hypothalamus regulate WIN 55212-2 [(4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one]-induced hypothermia.
TLDR
The results confirm the idea that CB(1) receptors mediate the hypothermic response to cannabinoid agonists and suggest that the POAH is the central locus for thermoregulation, and CB( 1) receptors within thePOAH are the primary mediators of cannabinoid-induced hypothermia.
Molecular characterization of a peripheral receptor for cannabinoids
TLDR
The cloning of a receptor for cannabinoids is reported that is not expressed in the brain but rather in macrophages in the marginal zone of spleen, which helps clarify the non-psychoactive effects of cannabinoids.
Synthesis and characterization of a peripherally restricted CB1 cannabinoid antagonist, URB447, that reduces feeding and body-weight gain in mice.
TLDR
The first mixed CB(1) antagonist/CB(2) agonist, URB447 is described, which lowers food intake and body-weight gain in mice without entering the brain or antagonizing centralCB(1)-dependent responses.
Conversion of 4-cyanomethyl-pyrazole-3-carboxamides into CB1 antagonists with lowered propensity to pass the blood-brain-barrier.
TLDR
A clear improvement in the peripheral profile over rimonabant was seen, although some contribution of central effect on the pronounced weight reduction in obese mice cannot be ruled out.
Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions
TLDR
This review will carefully examine the published literature and provide a perspective on what new tools and studies are required to address the peripheral site of action hypothesis.
Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism.
TLDR
2-AG activation of CB(2) receptors may contribute to the proliferative response of microglial cells, as occurs in neurodegenerative disorders.
Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis
TLDR
Experimental and clinical evidence supports the therapeutic potential of CB1 receptor antagonists to treat overweight/obesity, obesity-related cardiometabolic disorders, and substance abuse and Laboratory data suggest that CB2 receptor antagonists might be effective immunomodulatory and, perhaps, anti-inflammatory drugs.
Keynote review: Medicinal chemistry strategies to CB1 cannabinoid receptor antagonists.
TLDR
Besides novel compound classes that were identified in screening, rational medicinal chemistry approaches such as conformational constraint and scaffold hopping have been successfully applied and provided insight into crucial receptor-ligand interaction points thereby leading to a general CB(1) inverse agonist pharmacophore model.
International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors
TLDR
It is considered premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification, because pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging and other kinds of supporting evidence are still lacking.
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