Details of the Drug

General Information of Drug (ID: DMLZIT2)

• Drug Name: Dexniguldipine
• Synonyms: Dexniguldipine hydrochloride; BY-935; B-8509-035; B-859-35

Indication

Disease Entry	ICD 11	Status	REF
Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 2	[1], [2]

• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 3:
  Molecular Weight (mw); 609.7
  Topological Polar Surface Area (xlogp); 6.8
  Rotatable Bond Count (rotbonds); 11
  Hydrogen Bond Donor Count (hbonddonor); 1
  Hydrogen Bond Acceptor Count (hbondacc); 8
• ADMET Property:
  Clearance: The drug present in the plasma can be removed from the body at the rate of 9.3 mL/min/kg [3]
  Half-life: The concentration or amount of drug in body reduced by one-half in 22 hours [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 8.4 L/kg [3]
• Chemical Identifiers:
  Formula: C36H39N3O6
  IUPAC Name: 5-O-[3-(4,4-diphenylpiperidin-1-yl)propyl] 3-O-methyl (4R)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
  Canonical SMILES: CC1=C([C@H](C(=C(N1)C)C(=O)OCCCN2CCC(CC2)(C3=CC=CC=C3)C4=CC=CC=C4)C5=CC(=CC=C5)[N+](=O)[O-])C(=O)OC
  InChI: InChI=1S/C36H39N3O6/c1-25-31(34(40)44-3)33(27-12-10-17-30(24-27)39(42)43)32(26(2)37-25)35(41)45-23-11-20-38-21-18-36(19-22-38,28-13-6-4-7-14-28)29-15-8-5-9-16-29/h4-10,12-17,24,33,37H,11,18-23H2,1-3H3/t33-/m1/s1
  InChIKey: SVJMLYUFVDMUHP-MGBGTMOVSA-N
• Cross-matching ID:
  PubChem CID: 6918097
  ChEBI ID: CHEBI:103932
  CAS Number: 120054-86-6
  DrugBank ID: DB14068
  TTD ID: D0B1MJ
  VARIDT ID: DR01387
  INTEDE ID: DR0473

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Multidrug resistance protein 3 (ABCB4)	TTJUXV6	MDR3_HUMAN	Modulator	[4]

Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[5]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Substrate	[6]
Steroid 17-alpha-monooxygenase (CYP17A1)	DEX2KIA	CP17A_HUMAN	Substrate	[7]

References

• [1] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 463).
• [2] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002528)
• [3] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [4] Mechanism of action of dexniguldipine-HCl (B8509-035), a new potent modulator of multidrug resistance. Biochem Pharmacol. 1995 Mar 1;49(5):603-9.
• [5] Fingerprint-based in silico models for the prediction of P-glycoprotein substrates and inhibitors. Bioorg Med Chem. 2012 Sep 15;20(18):5388-95.
• [6] Integrated analysis on the physicochemical properties of dihydropyridine calcium channel blockers in grapefruit juice interactions. Curr Pharm Biotechnol. 2012 Jul;13(9):1705-17.
• [7] In vitro metabolism of dexamethasone (DEX) in human liver and kidney: the involvement of CYP3A4 and CYP17 (17,20 LYASE) and molecular modelling studies. Biochem Pharmacol. 1997 Sep 1;54(5):605-11.
• [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] Identifying susceptibility genes for prostate cancer--a family-based association study of polymorphisms in CYP17, CYP19, CYP11A1, and LH-beta. Cancer Epidemiol Biomarkers Prev. 2005 Aug;14(8):2035-9.
• [18] Contribution of human hepatic cytochrome P450s and steroidogenic CYP17 to the N-demethylation of aminopyrine. Xenobiotica. 1999 Feb;29(2):187-93.
• [19] Transcriptional complexes at the CYP17 CRS. Endocr Res. 2002 Nov;28(4):551-8.
• [20] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [21] MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents. Cancer Chemother Pharmacol. 2009 Jun;64(1):183-8.
• [22] 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.
• [23] Folate transporter expression decreases in the human placenta throughout pregnancy and in pre-eclampsia. Pregnancy Hypertens. 2012 Apr;2(2):123-31.
• [24] Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm Res. 2001 Dec;18(12):1660-8.
• [25] Antiestrogens and steroid hormones: substrates of the human P-glycoprotein. Biochem Pharmacol. 1994 Jul 19;48(2):287-92.
• [26] 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.
• [27] Discovery of Encequidar, First-in-Class Intestine Specific P-glycoprotein Inhibitor. J Med Chem. 2021 Apr 8;64(7):3677-3693.
• [28] A Phase I trial of a potent P-glycoprotein inhibitor, zosuquidar trihydrochloride (LY335979), administered intravenously in combination with doxoru... Clin Cancer Res. 2004 May 15;10(10):3265-72.
• [29] Reversal of multidrug resistance by a novel quinoline derivative, MS-209. Cancer Chemother Pharmacol. 1995;35(4):271-7.
• [30] Evaluation of [11C]laniquidar as a tracer of P-glycoprotein: radiosynthesis and biodistribution in rats. Nucl Med Biol. 2009 Aug;36(6):643-9.