General Information of Drug (ID: DM52HUD)

Drug Name
Dexloxiglumide
Synonyms
Dexloxiglumide; 119817-90-2; (R)-4-(3,4-Dichlorobenzamido)-5-((3-methoxypropyl)(pentyl)amino)-5-oxopentanoic acid; UNII-69DY40RH9B; CR-2017; 69DY40RH9B; Dexloxiglumidum; Dexloxiglumida; Dexloxiglumide [INN]; Dexloxiglumidum [INN-Latin]; Dexloxiglumida [INN-Spanish]; PubChem16049; AC1Q3MXI; GTPL889; SCHEMBL366142; CHEMBL550781; AC1L24A8; DTXSID50152604; MolPort-006-170-001; CHEBI:135747; ZINC3801027; KS-000007QQ; AKOS000279054; PB12713; DB04856; CC-26372; AJ-45649; AK129760; AS-35102; KB-210163; AX8123879; CS-0054881; FT-0603098; Q-4119
Indication
Disease Entry ICD 11 Status REF
Pancreatic malfunction DC30-DC3Z Phase 2 [1]
Drug Type
Small molecular drug
Structure
3D MOL 2D MOL
#Ro5 Violations (Lipinski): 1 Molecular Weight (mw) 461.4
Topological Polar Surface Area (xlogp) 3.9
Rotatable Bond Count (rotbonds) 14
Hydrogen Bond Donor Count (hbonddonor) 2
Hydrogen Bond Acceptor Count (hbondacc) 5
ADMET Property
BDDCS Class
Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 1: high solubility and high permeability [2]
Clearance
The drug present in the plasma can be removed from the body at the rate of 3.7 mL/min/kg [3]
Half-life
The concentration or amount of drug in body reduced by one-half in 1.2 hours [3]
Unbound Fraction
The unbound fraction of drug in plasma is 0.024% [3]
Vd
Fluid volume that would be required to contain the amount of drug present in the body at the same concentration as in the plasma 0.18 L/kg [3]
Chemical Identifiers
Formula
C21H30Cl2N2O5
IUPAC Name
(4R)-4-[(3,4-dichlorobenzoyl)amino]-5-[3-methoxypropyl(pentyl)amino]-5-oxopentanoic acid
Canonical SMILES
CCCCCN(CCCOC)C(=O)[C@@H](CCC(=O)O)NC(=O)C1=CC(=C(C=C1)Cl)Cl
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
InChIKey
QNQZBKQEIFTHFZ-GOSISDBHSA-N
Cross-matching ID
PubChem CID
65937
ChEBI ID
CHEBI:135747
CAS Number
119817-90-2
DrugBank ID
DB04856
TTD ID
D0TL7L
INTEDE ID
DR0470

Molecular Interaction Atlas of This Drug


Drug Therapeutic Target (DTT)
DTT Name DTT ID UniProt ID MOA REF
Cholecystokinin receptor type A (CCKAR) TTCG0AL CCKAR_HUMAN Inhibitor [4]
Gastrin/cholecystokinin type B receptor (CCKBR) TTVFO0U GASR_HUMAN Inhibitor [5]

Drug-Metabolizing Enzyme (DME)
DME Name DME ID UniProt ID MOA REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Substrate [6]
Cytochrome P450 2C9 (CYP2C9) DE5IED8 CP2C9_HUMAN Substrate [6]
Cytochrome P450 3A5 (CYP3A5) DEIBDNY CP3A5_HUMAN Substrate [6]
Cytochrome P450 2B6 (CYP2B6) DEPKLMQ CP2B6_HUMAN Substrate [7]
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This Drug

Molecular Expression Atlas of This Drug

The Studied Disease Pancreatic malfunction
ICD Disease Classification DC30-DC3Z
Molecule Name Molecule Type Gene Name p-value Fold-Change Z-score
Gastrin/cholecystokinin type B receptor (CCKBR) DTT CCKBR 6.53E-01 1.00E-03 4.05E-03
Cytochrome P450 2B6 (CYP2B6) DME CYP2B6 1.25E-01 -7.02E-02 -2.81E-01
Cytochrome P450 3A5 (CYP3A5) DME CYP3A5 9.83E-01 3.44E-02 7.14E-02
Cytochrome P450 2C9 (CYP2C9) DME CYP2C9 2.84E-06 1.24E-01 6.31E-01
Cytochrome P450 3A4 (CYP3A4) DME CYP3A4 1.75E-01 3.78E-02 1.44E-01
Molecular Expression Atlas (MEA) Jump to Detail Molecular Expression Atlas of This Drug

References

1 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
2 BDDCS predictions, self-correcting aspects of BDDCS assignments, BDDCS assignment corrections, and classification for more than 175 additional drugs
3 Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
4 Full agonists of CCK8 containing a nonhydrolyzable sulfated tyrosine residue. J Med Chem. 1989 Feb;32(2):445-9.
5 Synthesis and stereochemical structure-activity relationships of 1,3-dioxoperhydropyrido[1,2-c]pyrimidine derivatives: potent and selective cholecy... J Med Chem. 1997 Oct 10;40(21):3402-7.
6 Pharmacokinetic profile of dexloxiglumide. Clin Pharmacokinet. 2006;45(12):1177-88.
7 Effect of azole antifungals ketoconazole and fluconazole on the pharmacokinetics of dexloxiglumide. Br J Clin Pharmacol. 2005 Nov;60(5):498-507.
8 Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer. 2007 Mar 1;109(5):957-65.
9 Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
10 Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.
11 Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
12 Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol. 2017 Dec;69(12):1762-1772.
13 Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012 Apr;165(8):2787-98.
14 Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
15 The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. Biochem Pharmacol. 1994 Jul 19;48(2):267-76.
16 Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
17 Drug related genetic polymorphisms affecting adverse reactions to methotrexate, vinblastine, doxorubicin and cisplatin in patients with urothelial cancer. J Urol. 2008 Dec;180(6):2389-95.
18 Human prostate CYP3A5: identification of a unique 5'-untranslated sequence and characterization of purified recombinant protein. Biochem Biophys Res Commun. 1999 Jul 14;260(3):676-81.
19 Polymorphisms in cytochrome P4503A5 (CYP3A5) may be associated with race and tumor characteristics, but not metabolism and side effects of tamoxifen in breast cancer patients. Cancer Lett. 2005 Jan 10;217(1):61-72.
20 Drug Interactions Flockhart Table
21 Induction of hepatic CYP2E1 by a subtoxic dose of acetaminophen in rats: increase in dichloromethane metabolism and carboxyhemoglobin elevation. Drug Metab Dispos. 2007 Oct;35(10):1754-8.
22 Urinary 6 beta-hydroxycortisol excretion in rheumatoid arthritis. Br J Rheumatol. 1997 Jan;36(1):54-8.
23 Clinical pharmacokinetics of imatinib. Clin Pharmacokinet. 2005;44(9):879-94.
24 Kinetics and regulation of cytochrome P450-mediated etoposide metabolism. Drug Metab Dispos. 2004 Sep;32(9):993-1000.
25 Differential mechanism-based inhibition of CYP3A4 and CYP3A5 by verapamil. Drug Metab Dispos. 2005 May;33(5):664-71.
26 Progesterone and testosterone hydroxylation by cytochromes P450 2C19, 2C9, and 3A4 in human liver microsomes. Arch Biochem Biophys. 1997 Oct 1;346(1):161-9.
27 Tamoxifen inhibits cytochrome P450 2C9 activity in breast cancer patients. J Chemother. 2006 Aug;18(4):421-4.
28 Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology. 2003 Aug;144(8):3382-98.
29 Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
30 Drug-drug interactions with imatinib: an observational study. Medicine (Baltimore). 2016 Oct;95(40):e5076.
31 Drug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A. Drug Metab Dispos. 2000 Feb;28(2):125-30.
32 New insights into the structural features and functional relevance of human cytochrome P450 2C9. Part I. Curr Drug Metab. 2009 Dec;10(10):1075-126.
33 A potential role for the estrogen-metabolizing cytochrome P450 enzymes in human breast carcinogenesis. Breast Cancer Res Treat. 2003 Dec;82(3):191-7.
34 A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother. 1998 May;32(5):554-63.
35 Effect of tamoxifen on the enzymatic activity of human cytochrome CYP2B6. J Pharmacol Exp Ther. 2002 Jun;301(3):945-52.
36 Hepatic metabolism of diclofenac: role of human CYP in the minor oxidative pathways. Biochem Pharmacol. 1999 Sep 1;58(5):787-96.
37 Insights into CYP2B6-mediated drug-drug interactions. Acta Pharm Sin B. 2016 Sep;6(5):413-425.
38 Drugs that may have potential CYP2B6 interactions.
39 Involvement of human cytochrome P450 2B6 in the omega- and 4-hydroxylation of the anesthetic agent propofol. Xenobiotica. 2007 Jul;37(7):717-24.
40 Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-butanone metabolism by cytochrome P450 2B6. Drug Metab Dispos. 2005 Dec;33(12):1760-4.
41 PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70.
42 Application of the relative activity factor approach in scaling from heterologously expressed cytochromes p450 to human liver microsomes: studies on amitriptyline as a model substrate. J Pharmacol Exp Ther. 2001 Apr;297(1):326-37.
43 Functional interactions between endocannabinoid and CCK neurotransmitter systems may be critical for extinction learning. Neuropsychopharmacology. 2009 Jan;34(2):509-21.
44 Comparison of postprandial and ceruletide serum bile acid stimulation in dogs. J Vet Intern Med. 2008 Jul-Aug;22(4):873-8.
45 Gastrazole (JB95008), a novel CCK2/gastrin receptor antagonist, in the treatment of advanced pancreatic cancer: results from two randomised controlled trials. Br J Cancer. 2006 April 24; 94(8): 1107-1115.
46 Effect of dexloxiglumide and spiroglumide, two new CCK-receptor antagonists, on gastric emptying and secretion in the rat: evaluation of their receptor selectivity in vivo. Aliment Pharmacol Ther. 1996 Jun;10(3):411-9.
47 The effect of glucagon-like peptide-1 on energy expenditure and substrate metabolism in humans. Int J Obes Relat Metab Disord. 2000 Mar;24(3):288-98.
48 Z-360, a novel cholecystokinin-2/gastrin receptor antagonist, inhibits gemcitabine-induced expression of the vascular endothelial growth factor gen... Biol Pharm Bull. 2010;33(2):216-22.
49 Selective action of a CCK-B/gastrin receptor antagonist, S-0509, on pentagastrin-, peptone meal- and beer-stimulated gastric acid secretion in dogs. Aliment Pharmacol Ther. 2000 Apr;14(4):479-88.
50 CCK-B receptor antagonist YF476 inhibits pancreatic enzyme secretion at a duodenal level in pigs. Scand J Gastroenterol. 2004 Sep;39(9):886-90.
51 Role of CCK/gastrin receptors in gastrointestinal/metabolic diseases and results of human studies using gastrin/CCK receptor agonists/antagonists in these diseases. Curr Top Med Chem. 2007; 7(12): 1211-1231.
52 Demonstration of new sites of expression of the CCK-B/gastrin receptor in pancreatic acinar AR42J cells using immunoelectron microscopy. Regul Pept. 1999 Oct 22;84(1-3):81-9.
53 Pharmacological properties of lorglumide as a member of a new class of cholecystokinin antagonists. Arzneimittelforschung. 1987 Nov;37(11):1265-8.
54 A cholecystokinin-1 receptor agonist (CCK-8) mediates increased permeability of brain barriers to leptin. Br J Pharmacol. 2008 Jul;154(5):1009-15.
55 Melatonin as modulator of pancreatic enzyme secretion and pancreatoprotector. J Physiol Pharmacol. 2007 Dec;58 Suppl 6:65-80.
56 Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2003 Jul-Aug;25(6):483-506.
57 Dual CCK-A and -B receptor antagonists (I) C9-methyl-1,4-benzodiazepines, Bioorg. Med. Chem. Lett. 7(2):169-174 (1997).
58 Obesity Pharmacotherapy: Current Perspectives and Future Directions. Curr Cardiol Rev. 2013 February; 9(1): 33-54.
59 Emerging drugs for obesity: linking novel biological mechanisms to pharmaceutical pipelines. Expert Opin Emerg Drugs. 2005 Aug;10(3):643-60.
60 US patent application no. 8,748,419, Antagonists.
61 Effect of T-0632, a cholecystokininA receptor antagonist, on experimental acute pancreatitis. Jpn J Pharmacol. 1997 Feb;73(2):105-12.
62 SR146131: a new potent, orally active, and selective nonpeptide cholecystokinin subtype 1 receptor agonist. I. In vitro studies. J Pharmacol Exp Ther. 1999 May;289(2):742-51.