Details of the Drug

General Information of Drug (ID: DMVR628)

Drug Name
Vindesine
Synonyms
DAVA; Vindesin; Vindesina; Vindesinum; Desacetylvinblastine amide; Lilly 112531; Vindesina [INN-Spanish]; Vindesinum [INN-Latin]; Vindesine (USAN/INN); Vindesine [USAN:BAN:INN]; Vindesine [USAN:INN:BAN]; 3-(Aminocarbonyl)-O(sup 4)-deacetyl-3-de(methoxycarbonyl)vincaleukoblastine; 3-(aminocarbonyl)-O(4)-deacetyl-3-de(methoxycarbonyl)vincaleukoblastine; 3-Carbamoyl-4-deacetyl-3-de(methoxycarbonyl)vincaleukoblastine; 3-carbamoyl-O(4)-deacetyl-3-de(methoxycarbonyl)vincaleukoblastine; Methyl (5S,7S,9S)-9-[(2b,3b,4b,5a,12b,19a)-3-carbamoyl-3,4-dihydroxy-16-methoxy-1-methyl-6,7-didehydroaspidospermidin-15-yl]-5-ethyl-5-hydroxy-1,4,5,6,7,8,9,10-octahydro-2H-3,7-methanoazacycloundecino[5,4-b]indole-9-carboxylate; Methyl (5S,7S,9S)-9-[(2beta,3beta,4beta,5alpha,12beta,19alpha)-3-carbamoyl-3,4-dihydroxy-16-methoxy-1-methyl-6,7-didehydroaspidospermidin-15-yl]-5-ethyl-5-hydroxy-1,4,5,6,7,8,9,10-octahydro-2H-3,7-methanoazacycloundecino[5,4-b]indole-9-carboxylate
Indication
Disease Entry ICD 11 Status REF
Acute lymphoblastic leukaemia 2A85 Approved [1], [2]
Therapeutic Class
Anticancer Agents
Drug Type
Small molecular drug
Structure
3D MOL 2D MOL
#Ro5 Violations (Lipinski): 1 Molecular Weight (mw) 753.9
Topological Polar Surface Area (xlogp) 2.7
Rotatable Bond Count (rotbonds) 7
Hydrogen Bond Donor Count (hbonddonor) 5
Hydrogen Bond Acceptor Count (hbondacc) 10
ADMET Property
Clearance
The drug present in the plasma can be removed from the body at the rate of 2.2 mL/min/kg [3]
Half-life
The concentration or amount of drug in body reduced by one-half in 24 hours [3]
Metabolism
The drug is metabolized via the hepatic [4]
MRTD
The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 0.14325 micromolar/kg/day [5]
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 5 L/kg [3]
Chemical Identifiers
Formula
C43H55N5O7
IUPAC Name
methyl (13S,15S,17S)-13-[(1R,9R,10S,11R,12R,19R)-10-carbamoyl-12-ethyl-10,11-dihydroxy-5-methoxy-8-methyl-8,16-diazapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-2,4,6,13-tetraen-4-yl]-17-ethyl-17-hydroxy-1,11-diazatetracyclo[13.3.1.04,12.05,10]nonadeca-4(12),5,7,9-tetraene-13-carboxylate
Canonical SMILES
CC[C@@]1(C[C@@H]2C[C@@](C3=C(CCN(C2)C1)C4=CC=CC=C4N3)(C5=C(C=C6C(=C5)[C@]78CCN9[C@H]7[C@@](C=CC9)([C@H]([C@@]([C@@H]8N6C)(C(=O)N)O)O)CC)OC)C(=O)OC)O
InChI
InChI=1S/C43H55N5O7/c1-6-39(52)21-25-22-42(38(51)55-5,33-27(13-17-47(23-25)24-39)26-11-8-9-12-30(26)45-33)29-19-28-31(20-32(29)54-4)46(3)35-41(28)15-18-48-16-10-14-40(7-2,34(41)48)36(49)43(35,53)37(44)50/h8-12,14,19-20,25,34-36,45,49,52-53H,6-7,13,15-18,21-24H2,1-5H3,(H2,44,50)/t25-,34+,35-,36-,39+,40-,41-,42+,43+/m1/s1
InChIKey
HHJUWIANJFBDHT-KOTLKJBCSA-N
Cross-matching ID
PubChem CID
40839
ChEBI ID
CHEBI:36373
CAS Number
53643-48-4
DrugBank ID
DB00309
TTD ID
D04RLY
VARIDT ID
DR00397
INTEDE ID
DR1693

Molecular Interaction Atlas of This Drug


Drug Therapeutic Target (DTT)
DTT Name DTT ID UniProt ID MOA REF
Tubulin beta (TUBB) TTYFKSZ NOUNIPROTAC Binder [6], [7]

Drug Transporter (DTP)
DTP Name DTP ID UniProt ID MOA REF
P-glycoprotein 1 (ABCB1) DTUGYRD MDR1_HUMAN Substrate [8]

Drug-Metabolizing Enzyme (DME)
DME Name DME ID UniProt ID MOA REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Substrate [9]
Cytochrome P450 3A5 (CYP3A5) DEIBDNY CP3A5_HUMAN Substrate [10]
Cytochrome P450 3A7 (CYP3A7) DERD86B CP3A7_HUMAN Substrate [10]
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This Drug

References

1 Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
2 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
3 Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
4 FDA approval: ado-trastuzumab emtansine for the treatment of patients with HER2-positive metastatic breast cancer. Clin Cancer Res. 2014 Sep 1;20(17):4436-41.
5 Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
6 Antiproliferating activity of the mitotic inhibitor pironetin against vindesine- and paclitaxel-resistant human small cell lung cancer H69 cells. Anticancer Res. 2007 Mar-Apr;27(2):729-36.
7 Gene signatures developed from patient tumor explants grown in nude mice to predict tumor response to 11 cytotoxic drugs. Cancer Genomics Proteomics. 2007 May-Jun;4(3):197-209.
8 Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
9 Human liver microsomal cytochrome P450 3A isozymes mediated vindesine biotransformation. Metabolic drug interactions. Biochem Pharmacol. 1993 Feb 24;45(4):853-61.
10 Structural perspectives of the CYP3A family and their small molecule modulators in drug metabolism. 2019, 3(3), 132-142.
11 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.
12 Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
13 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.
14 Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
15 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.
16 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.
17 Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
18 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.
19 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.
20 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.
21 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.
22 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.
23 Drug Interactions Flockhart Table
24 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.
25 Urinary 6 beta-hydroxycortisol excretion in rheumatoid arthritis. Br J Rheumatol. 1997 Jan;36(1):54-8.
26 Clinical pharmacokinetics of imatinib. Clin Pharmacokinet. 2005;44(9):879-94.
27 Kinetics and regulation of cytochrome P450-mediated etoposide metabolism. Drug Metab Dispos. 2004 Sep;32(9):993-1000.
28 Differential mechanism-based inhibition of CYP3A4 and CYP3A5 by verapamil. Drug Metab Dispos. 2005 May;33(5):664-71.
29 The role of cytochrome P450 3A (CYP3A) isoform(s) in oxidative metabolism of testosterone and benzphetamine in human adult and fetal liver. J Steroid Biochem Mol Biol. 1993 Jan;44(1):61-7.
30 Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
31 Prediction of cytochrome P450 3A inhibition by verapamil enantiomers and their metabolites. Drug Metab Dispos. 2004 Feb;32(2):259-66.
32 The role of human cytochrome P450 enzymes in the formation of 2-hydroxymetronidazole: CYP2A6 is the high affinity (low Km) catalyst. Drug Metab Dispos. 2013 Sep;41(9):1686-94.
33 MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents. Cancer Chemother Pharmacol. 2009 Jun;64(1):183-8.
34 Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
35 Folate transporter expression decreases in the human placenta throughout pregnancy and in pre-eclampsia. Pregnancy Hypertens. 2012 Apr;2(2):123-31.
36 Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm Res. 2001 Dec;18(12):1660-8.
37 Antiestrogens and steroid hormones: substrates of the human P-glycoprotein. Biochem Pharmacol. 1994 Jul 19;48(2):287-92.
38 Association of genetic polymorphisms in the influx transporter SLCO1B3 and the efflux transporter ABCB1 with imatinib pharmacokinetics in patients with chronic myeloid leukemia. Ther Drug Monit. 2011 Apr;33(2):244-50.
39 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
40 Flubendazole interferes with a wide spectrum of cell homeostatic mechanisms in Echinococcus granulosus protoscoleces. Parasitol Int. 2009 Sep;58(3):270-7.
41 Paclitaxel directly binds to Bcl-2 and functionally mimics activity of Nur77. Cancer Res. 2009 Sep 1;69(17):6906-14.
42 NPI-2358 is a tubulin-depolymerizing agent: in-vitro evidence for activity as a tumor vascular-disrupting agent. Anticancer Drugs. 2006 Jan;17(1):25-31.
43 Hydrophilic, pro-drug analogues of T138067 are efficacious in controlling tumor growth in vivo and show a decreased ability to cross the blood brain barrier. J Med Chem. 2001 Oct 25;44(22):3599-605.
44 Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
45 Total synthesis and biological evaluation of ustiloxin natural products and two analogs. Bioorg Med Chem Lett. 2006 Sep 15;16(18):4804-7.
46 The vascular disrupting agent BNC105 potentiates the efficacy of VEGF and mTOR inhibitors in renal and breast cancer.Cancer Biol Ther.2014;15(11):1552-60.
47 National Cancer Institute Drug Dictionary (drug id 598799).