Identification

Name
Dexloxiglumide
Accession Number
DB04856
Type
Small Molecule
Groups
Investigational
Description

Dexloxiglumide is a selective cholecystokinin type A (CCKA) receptor antagonist in phase III testing by Rottapharm in Europe only, as U.S. trials have been discontinued. As the D-isomer of loxiglumide, it retains all pharmacological properties of loxiglumide but is more potent.

Structure
Thumb
Synonyms
  • CR 2017
External IDs
CR-2017
Categories
UNII
69DY40RH9B
CAS number
119817-90-2
Weight
Average: 461.379
Monoisotopic: 460.153177494
Chemical Formula
C21H30Cl2N2O5
InChI Key
QNQZBKQEIFTHFZ-GOSISDBHSA-N
InChI
InChI=1S/C21H30Cl2N2O5/c1-3-4-5-11-25(12-6-13-30-2)21(29)18(9-10-19(26)27)24-20(28)15-7-8-16(22)17(23)14-15/h7-8,14,18H,3-6,9-13H2,1-2H3,(H,24,28)(H,26,27)/t18-/m1/s1
IUPAC Name
(4R)-4-[(3,4-dichlorophenyl)formamido]-4-[(3-methoxypropyl)(pentyl)carbamoyl]butanoic acid
SMILES
CCCCCN(CCCOC)C(=O)[[email protected]@H](CCC(O)=O)NC(=O)C1=CC(Cl)=C(Cl)C=C1

Pharmacology

Indication

For the treatment of Irritable Bowel Syndrome (IBS) and Gastroesophageal Reflux Disease (GERD).

Structured Indications
Not Available
Pharmacodynamics

Dexloxiglumide is a selective cholecystokinin type A (CCKA) receptor antagonist. In October 2003, following the completion of two phase III clinical studies involving dexloxiglumide in women with constipation-predominant irritable bowel syndrome (IBS), Forest Laboratories decided to discontinue development of the drug for this indication. The results of the studies showed that dexloxiglumide did not show statistically significant favorability over placebo. Rotta Research is continuing a phase III trial of a different design in Europe for the IBS indication and also for gastroesophogeal reflux disease.

Mechanism of action

CCKA antagonists target receptors in the gastrointestinal system to increase gastric emptying and intestinal motility, as well as modulate intestinal sensitivity to distension.

TargetActionsOrganism
UCholecystokinin receptor type ANot AvailableHuman
Absorption

Rapidly and extensively absorbed after single oral administration in humans with an absolute bioavailability of 48%. The incomplete bioavailability is due to both incomplete absorption and hepatic first-pass effect.

Volume of distribution
Not Available
Protein binding

94-98%

Metabolism

Cytochrome P450 (CYP) 3A4/5 and CYP2C9 have been implicated in the metabolism of dexloxiglumide to produce O-demethyl dexloxi-glumide. This metabolite is further oxidised to dexloxiglumide carboxylic acid. These two major metabolites (accounting for up to 50% of dexloxiglumide elimination) have been identified. However, in human plasma the unchanged drug represents the major (up to 91%) component of the metabolic profile. The parent drug is believed to be the major contributor to the efficacy of the compound, since its major metabolites are pharmacologically inactive.

Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Persiani S, D'Amato M, Jakate A, Roy P, Wangsa J, Kapil R, Rovati LC: Pharmacokinetic profile of dexloxiglumide. Clin Pharmacokinet. 2006;45(12):1177-88. [PubMed:17112294]
  2. Maselli MA, Mennuni L: CCK1 receptor antagonist, dexloxiglumide: effects on human isolated gallbladder. Potential clinical applications. Minerva Gastroenterol Dietol. 2003 Sep;49(3):211-6. [PubMed:16484960]
External Links
PubChem Compound
65937
PubChem Substance
175426866
ChemSpider
59342
ChEBI
135747
ChEMBL
CHEMBL550781

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentIndigestion1
3CompletedTreatmentIrritable Bowel Syndrome (IBS)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00555 mg/mLALOGPS
logP3.23ALOGPS
logP3.37ChemAxon
logS-4.9ALOGPS
pKa (Strongest Acidic)4.05ChemAxon
pKa (Strongest Basic)-1ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area95.94 Å2ChemAxon
Rotatable Bond Count14ChemAxon
Refractivity117.01 m3·mol-1ChemAxon
Polarizability47.88 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.5738
Blood Brain Barrier-0.7306
Caco-2 permeable-0.8957
P-glycoprotein substrateSubstrate0.8266
P-glycoprotein inhibitor INon-inhibitor0.5658
P-glycoprotein inhibitor IINon-inhibitor0.6272
Renal organic cation transporterNon-inhibitor0.868
CYP450 2C9 substrateNon-substrate0.8529
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.5
CYP450 1A2 substrateNon-inhibitor0.788
CYP450 2C9 inhibitorNon-inhibitor0.8266
CYP450 2D6 inhibitorNon-inhibitor0.8319
CYP450 2C19 inhibitorNon-inhibitor0.7627
CYP450 3A4 inhibitorNon-inhibitor0.7224
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7843
Ames testNon AMES toxic0.9132
CarcinogenicityNon-carcinogens0.9188
BiodegradationNot ready biodegradable0.9931
Rat acute toxicity2.1985 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9558
hERG inhibition (predictor II)Inhibitor0.5705
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 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

Taxonomy

Description
This compound belongs to the class of organic compounds known as glutamic acid and derivatives. These are compounds containing glutamic acid or a derivative thereof resulting from reaction of glutamic acid at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Glutamic acid and derivatives
Alternative Parents
N-acyl-alpha amino acids and derivatives / Hippuric acids and derivatives / Alpha amino acid amides / 3-halobenzoic acids and derivatives / 4-halobenzoic acids and derivatives / Benzoyl derivatives / Dichlorobenzenes / Aryl chlorides / N-acyl amines / Tertiary carboxylic acid amides
show 10 more
Substituents
Glutamic acid or derivatives / Hippuric acid or derivatives / N-acyl-alpha amino acid or derivatives / Alpha-amino acid amide / Halobenzoic acid or derivatives / 4-halobenzoic acid or derivatives / 3-halobenzoic acid or derivatives / Benzamide / Benzoic acid or derivatives / Benzoyl
show 26 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Peptide binding
Specific Function
Receptor for cholecystokinin. Mediates pancreatic growth and enzyme secretion, smooth muscle contraction of the gall bladder and stomach. Has a 1000-fold higher affinity for CCK rather than for gas...
Gene Name
CCKAR
Uniprot ID
P32238
Uniprot Name
Cholecystokinin receptor type A
Molecular Weight
47840.645 Da
References
  1. Persiani S, D'Amato M, Jakate A, Roy P, Wangsa J, Kapil R, Rovati LC: Pharmacokinetic profile of dexloxiglumide. Clin Pharmacokinet. 2006;45(12):1177-88. [PubMed:17112294]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
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. Hall M, Persiani S, Cheung YL, Matthews A, Cybulski ZR, Holding JD, Kapil R, D'Amato M, Makovec F, Rovati LC: Interaction of dexloxiglumide, a cholecystokinin type-1 receptor antagonist, with human cytochromes P450. Biopharm Drug Dispos. 2004 May;25(4):163-76. [PubMed:15108219]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Hall M, Persiani S, Cheung YL, Matthews A, Cybulski ZR, Holding JD, Kapil R, D'Amato M, Makovec F, Rovati LC: Interaction of dexloxiglumide, a cholecystokinin type-1 receptor antagonist, with human cytochromes P450. Biopharm Drug Dispos. 2004 May;25(4):163-76. [PubMed:15108219]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Oxygen binding
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 oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Hall M, Persiani S, Cheung YL, Matthews A, Cybulski ZR, Holding JD, Kapil R, D'Amato M, Makovec F, Rovati LC: Interaction of dexloxiglumide, a cholecystokinin type-1 receptor antagonist, with human cytochromes P450. Biopharm Drug Dispos. 2004 May;25(4):163-76. [PubMed:15108219]

Drug created on October 18, 2007 18:07 / Updated on November 09, 2017 03:48