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Details

Stereochemistry ABSOLUTE
Molecular Formula C36H39N3O6.ClH
Molecular Weight 646.172
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of DEXNIGULDIPINE HYDROCHLORIDE

SMILES

Cl.COC(=O)C1=C(C)NC(C)=C([C@@H]1C2=CC(=CC=C2)[N+]([O-])=O)C(=O)OCCCN3CCC(CC3)(C4=CC=CC=C4)C5=CC=CC=C5

InChI

InChIKey=MHOSUIMBPQVOEU-MGDILKBHSA-N
InChI=1S/C36H39N3O6.ClH/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;1H/t33-;/m1./s1

HIDE SMILES / InChI

Molecular Formula ClH
Molecular Weight 36.461
Charge 0
Count
MOL RATIO 1 MOL RATIO (average)
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Molecular Formula C36H39N3O6
Molecular Weight 609.7114
Charge 0
Count
MOL RATIO 1 MOL RATIO (average)
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Description

Dexniguldipine (B8509-035, (-)-(R)-niguldipine) is a new dihydropyridine derivative, that exerts selective antiproliferative activity in a variety of tumor models and, in addition, has a high potency in overcoming multidrug resistance. Dexniguldipine is ( - )-(R)-enantiomer of niguldipine, of which the ( )-(S)-enantiomer shows pronounced cardiovascular hypotensive activity due to its high affinity for the voltage-dependent Ca2 channel. As compared with the (S)-enantiomer, the (R)-enantiomer has a 40-fold lower affinity for the Ca 2 channel and, accordingly, only minimal hypotensive activity in animal pharmacology models. Dexniguldipine have shown antiproliferative activity in several tumor cell lines, but the concentrations necessary to inhibit growth have varied by several orders of magnitude between cell lines. Initial results of preclinical investigations for the evaluation of the mechanism of its antiproliferative activity demonstrate that dexniguldipine interferes with intracellular signal transduction by affecting phosphoinositol pathways, protein kinase C expression, and intracellular Ca 2 metabolism. In a series of human tumor xenografts in vitro, dexniguldipine demonstrated selective antiproliferative activity against several tumor types, e.g., melanoma and renal-cell carcinoma. Striking results were obtained in a hamster model, in which neuroendocrine lung tumors could be completely eradicated by 20 weeks of oral treatment with 32.5mg/kg dexniguldipine, whereas Clara-cell-type lung tumors were not affected. In in vitro studies, dexniguldipine has been found to bind to P-glycoprotein (P-gp) and to enhance the cytotoxicity of chemotherapeutic agents such as doxorubicin and etoposide in several cell lines The synergistic effect may well be associated with the reversal of multidrug resistance (MDR) related to the activity of P-gp. In the clinical therapy of cancer, resistance to many cytostatic drugs is a major cause of treatment failure. However, the high potency of dexniguldipine (about 10-fold as compared with that of verapamil in vitro) and its low cardiovascular activity provide the opportunity to achieve blood or tumor concentrations that might be high enough to overcome Mdr 1 resistance in patients without producing dose-limiting cardiovascular effects.

Originator

Approval Year

Targets

Primary TargetPharmacologyConditionPotency
2.3 µM [Ki]
59.7 nM [Ki]
1.9 µM [Ki]
4.7 nM [Ki]
56.0 nM [Ki]
170.0 nM [Ki]

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown
Primary
Unknown

Overview

CYP3A4CYP2C9CYP2D6hERG

OverviewOther

Other InhibitorOther SubstrateOther Inducer


Drug as perpetrator​

Drug as victim

PubMed

Patents

Sample Use Guides

In Vivo Use Guide
Dexniguldipine was given as soft gelatin capsules containing 20, 100, or 250 mg, respectively. Patients in group I (20 mg) and group II (40 mg) received a single dose. Patients in group III-IX (100mg-2500mg) took dexniguldipine once daily in the morning before breakfast for 7 days
Route of Administration: Oral
In Vitro Use Guide
Multidrug-resistant cell line HeLa-MDR-1 were used for activity evaluation. HeLa-MDR-1 was obtained by transfection of human HeLa S3 (HeLa-WT) cervix carcinoma cells with an MDR-1 gene using the expression vector construct pSKl.MDR. The expression of P-glycoprotein in the HeLa-MDR-1 cells was approximately 31 times higher than in HeLa-WT. HeLa-MDR-1 cells were grown in the presence of 240 ng/mL colchicine except at the time of the experiments. The modulation by dexniguldipine (1 mkM) of the sensitivity of the HeLa-MDR-1 cell lines to Adriamycin, vinblastine or etoposide was determined by MIT assay following incubation for 72 hr in the presence of the drugs.
Substance Class Chemical
Record UNII
0642TZ1JZN
Record Status Validated (UNII)
Record Version