Identification

Name
Rimonabant
Accession Number
DB06155
Type
Small Molecule
Groups
Approved, Investigational
Description

Rimonabant is an anorectic anti-obesity drug produced and marketed by Sanofi-Aventis. It is an inverse agonist for the cannabinoid receptor CB1. Its main avenue of effect is reduction in appetite. Rimonabant is the first selective CB1 receptor blocker to be approved for use anywhere in the world. Rimonabant is approved in 38 countries including the E.U., Mexico, and Brazil. It was rejected for approval for use in the United States. This decision was made after a U.S. advisory panel recommended the medicine not be approved because it may increase suicidal thinking and depression.

Structure
Thumb
Synonyms
Not Available
External IDs
SR141716 / SR141716A
Product Ingredients
IngredientUNIICASInChI Key
Rimonabant hydrochlorideHL0V2LQZ09158681-13-1REOYOKXLUFHOBV-UHFFFAOYSA-N
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
AcompliaRimonabant (20 mg)Tablet, film coatedOralSanofi Aventis2006-06-192009-01-30Eu
AcompliaRimonabant (20 mg)Tablet, film coatedOralSanofi Aventis2006-06-192009-01-30Eu
AcompliaRimonabant (20 mg)Tablet, film coatedOralSanofi Aventis2006-06-192009-01-30Eu
AcompliaRimonabant (20 mg)Tablet, film coatedOralSanofi Aventis2006-06-192009-01-30Eu
AcompliaRimonabant (20 mg)Tablet, film coatedOralSanofi Aventis2006-06-192009-01-30Eu
AcompliaRimonabant (20 mg)Tablet, film coatedOralSanofi Aventis2006-06-192009-01-30Eu
AcompliaRimonabant (20 mg)Tablet, film coatedOralSanofi Aventis2006-06-192009-01-30Eu
AcompliaRimonabant (20 mg)Tablet, film coatedOralSanofi Aventis2006-06-192009-01-30Eu
AcompliaRimonabant (20 mg)Tablet, film coatedOralSanofi Aventis2006-06-192009-01-30Eu
AcompliaRimonabant (20 mg)Tablet, film coatedOralSanofi Aventis2006-06-192009-01-30Eu
International/Other Brands
Acomplia / Rimoslim / Riobant / Slimona / Zimulti
Categories
UNII
RML78EN3XE
CAS number
168273-06-1
Weight
Average: 463.787
Monoisotopic: 462.078094435
Chemical Formula
C22H21Cl3N4O
InChI Key
JZCPYUJPEARBJL-UHFFFAOYSA-N
InChI
InChI=1S/C22H21Cl3N4O/c1-14-20(22(30)27-28-11-3-2-4-12-28)26-29(19-10-9-17(24)13-18(19)25)21(14)15-5-7-16(23)8-6-15/h5-10,13H,2-4,11-12H2,1H3,(H,27,30)
IUPAC Name
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide
SMILES
CC1=C(N(N=C1C(=O)NN1CCCCC1)C1=C(Cl)C=C(Cl)C=C1)C1=CC=C(Cl)C=C1

Pharmacology

Indication

For use in conjunction with diet and exercise for patients with a body mass index greater than 30 kg/m2, or patients wih a BMI greater than 27 kg/m2 with associated risk factors, such as type 2 diabetes or dyslipidaemia.

Pharmacodynamics

In the RIO-North America trial, 3040 patients were randomized to receive either placebo or one of two doses of rimonabant (5 mg or 20 mg per day). Patients taking 20 mg rimonabant had significant weigh loss, decrease in waist circumference, improved insulin sensitivity, and increases in HDL cholesterol, compared to patients on placebo.

Mechanism of action

Rimonabant is a specific CB1 cannabinoid receptor antagonist. There is considerable evidence that the endocannabinoid (endogenous cannabinoid) system plays a significant role in appetitive drive and associated behaviours. It is therefore reasonable to hypothesize that the attenuation of the activity of this system would have therapeutic benefit in treating disorders that might have a component of excess appetitive drive or over-activity of the endocannabinoid system, such as obesity, ethanol and other drug abuse, and a variety of central nervous system and other disorders.

TargetActionsOrganism
ACannabinoid receptor 1
antagonist
Human
UG-protein coupled receptor 55Not AvailableHuman
Absorption

Undetermined

Volume of distribution
Not Available
Protein binding

Almost 100%

Metabolism

Hepatic, CYP3A4 involved.

Route of elimination
Not Available
Half life

6 to 9 days with normal BMI and 16 days if BMI is greater than 30

Clearance
Not Available
Toxicity

Almost twice as many people discontinued rimonabant compared with placebo because of adverse events (13.8% vs. 7.2%). These consistently involved psychiatric disorders (8.5% vs. 3.2%), including depression and anxiety. Other common side effects included insomnia, nausea, vomiting, diarrhoea and fatigue.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcebutololThe risk or severity of Tachycardia can be increased when Rimonabant is combined with Acebutolol.
AcetazolamideThe metabolism of Rimonabant can be decreased when combined with Acetazolamide.
Acetyl sulfisoxazoleThe metabolism of Rimonabant can be decreased when combined with Acetyl sulfisoxazole.
AlbendazoleThe metabolism of Rimonabant can be decreased when combined with Albendazole.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Rimonabant.
AlfentanilThe metabolism of Alfentanil can be decreased when combined with Rimonabant.
AlfuzosinThe metabolism of Rimonabant can be decreased when combined with Alfuzosin.
AlmotriptanThe metabolism of Rimonabant can be decreased when combined with Almotriptan.
AlosetronThe metabolism of Rimonabant can be decreased when combined with Alosetron.
AlprazolamThe metabolism of Alprazolam can be decreased when combined with Rimonabant.
Food Interactions
Not Available

References

Synthesis Reference

Alain Alcade, Gilles Anne-Archard, Corinne Gavory, Olivier Monnier, "Polymorphic form of rimonabant method for preparing it and pharmaceutical compositions containing it." U.S. Patent US20050043356, issued February 24, 2005.

US20050043356
General References
  1. Gelfand EV, Cannon CP: Rimonabant: a selective blocker of the cannabinoid CB1 receptors for the management of obesity, smoking cessation and cardiometabolic risk factors. Expert Opin Investig Drugs. 2006 Mar;15(3):307-15. [PubMed:16503766]
  2. Xie S, Furjanic MA, Ferrara JJ, McAndrew NR, Ardino EL, Ngondara A, Bernstein Y, Thomas KJ, Kim E, Walker JM, Nagar S, Ward SJ, Raffa RB: The endocannabinoid system and rimonabant: a new drug with a novel mechanism of action involving cannabinoid CB1 receptor antagonism--or inverse agonism--as potential obesity treatment and other therapeutic use. J Clin Pharm Ther. 2007 Jun;32(3):209-31. [PubMed:17489873]
  3. Cahill K, Ussher M: Cannabinoid type 1 receptor antagonists (rimonabant) for smoking cessation. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD005353. [PubMed:17943852]
  4. Maldonado R, Valverde O, Berrendero F: Involvement of the endocannabinoid system in drug addiction. Trends Neurosci. 2006 Apr;29(4):225-32. Epub 2006 Feb 17. [PubMed:16483675]
  5. Deadwyler SA, Goonawardena AV, Hampson RE: Short-term memory is modulated by the spontaneous release of endocannabinoids: evidence from hippocampal population codes. Behav Pharmacol. 2007 Sep;18(5-6):571-80. [PubMed:17762525]
  6. Huestis MA, Gorelick DA, Heishman SJ, Preston KL, Nelson RA, Moolchan ET, Frank RA: Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch Gen Psychiatry. 2001 Apr;58(4):322-8. [PubMed:11296091]
External Links
Human Metabolome Database
HMDB0015623
KEGG Drug
D05731
KEGG Compound
C14319
PubChem Compound
104850
PubChem Substance
99443236
ChemSpider
94641
BindingDB
21278
ChEBI
34967
ChEMBL
CHEMBL111
Therapeutic Targets Database
DNC001371
PharmGKB
PA152407999
IUPHAR
745
Guide to Pharmacology
GtP Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Rimonabant
ATC Codes
A08AX01 — Rimonabant
MSDS
Download (69.1 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedOtherCannabis / Dependence1
1CompletedTreatmentPain1
2CompletedTreatmentAlcohol Drinking / Healthy Volunteers1
2CompletedTreatmentBMI >30 kg/m21
2TerminatedTreatmentBMI >30 kg/m2 / High Blood Pressure (Hypertension) / Schizoaffective Disorders / Schizophrenic Disorders / Smoking1
3CompletedPreventionBMI >30 kg/m2 / Obese experiencing rapid weight loss1
3CompletedTreatmentBMI >30 kg/m23
3CompletedTreatmentBMI >30 kg/m2 / Diabetes Mellitus, Non-Insulin-Dependent / Obesity in Diabetes1
3CompletedTreatmentBMI >30 kg/m2 / Dyslipidemias2
3CompletedTreatmentBMI >30 kg/m2 / Eating Disorders1
3CompletedTreatmentCessation, Smoking4
3CompletedTreatmentCoronary Artery Atherosclerosis1
3CompletedTreatmentMaintenance of Smoking Cessation1
3CompletedTreatmentMetabolic Syndromes1
3CompletedTreatmentType 2 Diabetes Mellitus3
3TerminatedTreatmentArteriosclerosis / BMI >30 kg/m2 / Carotid Artery Plaque / Metabolic Syndromes1
3TerminatedTreatmentBMI >30 kg/m23
3TerminatedTreatmentBMI >30 kg/m2 / Dyslipidemias1
3TerminatedTreatmentBMI >30 kg/m2 / Dyslipidemias / Microalbuminuria / Type 2 Diabetes Mellitus1
3TerminatedTreatmentBMI >30 kg/m2 / Type 2 Diabetes Mellitus2
3TerminatedTreatmentBMI >30 kg/m2 / Obese experiencing rapid weight loss1
3TerminatedTreatmentCardiovascular Disease (CVD)1
3TerminatedTreatmentFatty Liver2
3TerminatedTreatmentPrediabetic State1
3TerminatedTreatmentType 2 Diabetes Mellitus2
3Unknown StatusTreatmentPrader-Willi Syndrome1
3WithdrawnTreatmentType 2 Diabetes Mellitus1
4TerminatedBasic ScienceBMI >30 kg/m21
4Unknown StatusPreventionAtherosclerosis / Cardiovascular Disease (CVD)1
Not AvailableCompletedNot AvailableCarotid Atherosclerosis / Metabolic Syndromes / Strokes / Type 2 Diabetes Mellitus1
Not AvailableCompletedDiagnosticCannabis Dependence / Cannabis Withdrawal1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral20 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.002 mg/mLALOGPS
logP5.47ALOGPS
logP5.91ChemAxon
logS-5.4ALOGPS
pKa (Strongest Acidic)12.42ChemAxon
pKa (Strongest Basic)1.68ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area50.16 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity122.83 m3·mol-1ChemAxon
Polarizability47.96 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.8799
Caco-2 permeable-0.6262
P-glycoprotein substrateSubstrate0.5723
P-glycoprotein inhibitor IInhibitor0.5864
P-glycoprotein inhibitor IINon-inhibitor0.9065
Renal organic cation transporterNon-inhibitor0.5902
CYP450 2C9 substrateNon-substrate0.6828
CYP450 2D6 substrateNon-substrate0.7198
CYP450 3A4 substrateSubstrate0.734
CYP450 1A2 substrateNon-inhibitor0.6107
CYP450 2C9 inhibitorInhibitor0.8837
CYP450 2D6 inhibitorInhibitor0.8367
CYP450 2C19 inhibitorInhibitor0.885
CYP450 3A4 inhibitorNon-inhibitor0.7535
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.9216
Ames testNon AMES toxic0.5896
CarcinogenicityNon-carcinogens0.7543
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.5418 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.683
hERG inhibition (predictor II)Inhibitor0.7958
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-03xr-0007900000-a3e664246f26a3081b28

Taxonomy

Description
This compound belongs to the class of organic compounds known as phenylpyrazoles. These are compounds containing a phenylpyrazole skeleton, which consists of a pyrazole bound to a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Azoles
Sub Class
Pyrazoles
Direct Parent
Phenylpyrazoles
Alternative Parents
Dichlorobenzenes / Piperidines / Aryl chlorides / Heteroaromatic compounds / Hydrazones / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds / Organochlorides / Hydrocarbon derivatives
Substituents
Phenylpyrazole / 1,3-dichlorobenzene / Chlorobenzene / Halobenzene / Aryl chloride / Aryl halide / Monocyclic benzene moiety / Benzenoid / Piperidine / Heteroaromatic compound
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
pyrazoles, ring assembly (CHEBI:34967)

Targets

Details
1. Cannabinoid receptor 1
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Drug binding
Specific Function
Involved in cannabinoid-induced CNS effects. Acts by inhibiting adenylate cyclase. Could be a receptor for anandamide. Inhibits L-type Ca(2+) channel current. Isoform 2 and isoform 3 have altered l...
Gene Name
CNR1
Uniprot ID
P21554
Uniprot Name
Cannabinoid receptor 1
Molecular Weight
52857.365 Da
References
  1. Shire D, Calandra B, Delpech M, Dumont X, Kaghad M, Le Fur G, Caput D, Ferrara P: Structural features of the central cannabinoid CB1 receptor involved in the binding of the specific CB1 antagonist SR 141716A. J Biol Chem. 1996 Mar 22;271(12):6941-6. [PubMed:8636122]
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
G-protein coupled receptor activity
Specific Function
May be involved in hyperalgesia associated with inflammatory and neuropathic pain (By similarity). Receptor for L-alpha-lysophosphatidylinositol (LPI). LPI induces Ca(2+) release from intracellular...
Gene Name
GPR55
Uniprot ID
Q9Y2T6
Uniprot Name
G-protein coupled receptor 55
Molecular Weight
36637.12 Da
References
  1. Kapur A, Zhao P, Sharir H, Bai Y, Caron MG, Barak LS, Abood ME: Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands. J Biol Chem. 2009 Oct 23;284(43):29817-27. doi: 10.1074/jbc.M109.050187. Epub 2009 Sep 1. [PubMed:19723626]

Enzymes

Details
1. Cytochrome P450 3A4
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Leite CE, Mocelin CA, Petersen GO, Leal MB, Thiesen FV: Rimonabant: an antagonist drug of the endocannabinoid system for the treatment of obesity. Pharmacol Rep. 2009 Mar-Apr;61(2):217-24. [PubMed:19443932]
  2. Lazary J, Juhasz G, Hunyady L, Bagdy G: Personalized medicine can pave the way for the safe use of CB(1) receptor antagonists. Trends Pharmacol Sci. 2011 May;32(5):270-80. doi: 10.1016/j.tips.2011.02.013. Epub 2011 Apr 16. [PubMed:21497918]

Drug created on February 14, 2008 10:07 / Updated on October 01, 2018 16:44