Details of the Drug

General Information of Drug (ID: DMZU5JP)

• Drug Name: Flunarizine
• Synonyms: Flufenal; Flunarizin; Flunarizina; Flunarizinum; Fluvert; Issium; Sibelium; Vertix; Zinasen; Apo-flunarizine capsules; Flunarizina [INN-Spanish]; Flunarizine (INN); Flunarizine [INN:BAN]; Flunarizinum [INN-Latin]; Novo-Flunarizine; R-14950; Sibelium (TN); (E)-1-(Bis(4-fluorophenyl)methyl)-4-(3-phenyl-2-propenyl)piperazine; (E)-1-[Bis-(p-fluorophenyl)methyl]-4-cinnamylpiperazine; 1-(Bis(4-fluorophenyl)methyl)-4-cinnamylpiperazine; 1-[bis(4-fluorophenyl)methyl]-4-(3-phenylprop-2-en-1-yl)piperazine; 1-[bis(4-fluorophenyl)methyl]-4-[(E)-3-phenylprop-2-enyl]piperazine

Indication

Disease Entry	ICD 11	Status	REF
Migraine	8A80	Approved	[1]

• Therapeutic Class: Anticonvulsants
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 1:
  Molecular Weight (mw); 404.5
  Logarithm of the Partition Coefficient (xlogp); 6
  Rotatable Bond Count (rotbonds); 6
  Hydrogen Bond Donor Count (hbonddonor); 0
  Hydrogen Bond Acceptor Count (hbondacc); 4
• ADMET Property:
  Absorption: The oral absorption of drug is 85% []
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 2: low solubility and high permeability [2]
  Elimination: 0.2% of drug is excreted from urine in the unchanged form [2]
  Half-life: The concentration or amount of drug in body reduced by one-half in 18 days [3]
  Metabolism: The drug is metabolized via the hepatic []
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 0.3532 micromolar/kg/day [4]
  Water Solubility: The ability of drug to dissolve in water is measured as 0.0165 mg/mL [2]
• Chemical Identifiers:
  Formula: C26H26F2N2
  IUPAC Name: 1-[bis(4-fluorophenyl)methyl]-4-[(E)-3-phenylprop-2-enyl]piperazine
  Canonical SMILES: C1CN(CCN1C/C=C/C2=CC=CC=C2)C(C3=CC=C(C=C3)F)C4=CC=C(C=C4)F
  InChI: InChI=1S/C26H26F2N2/c27-24-12-8-22(9-13-24)26(23-10-14-25(28)15-11-23)30-19-17-29(18-20-30)16-4-7-21-5-2-1-3-6-21/h1-15,26H,16-20H2/b7-4+
  InChIKey: SMANXXCATUTDDT-QPJJXVBHSA-N
• Cross-matching ID:
  PubChem CID: 941361
  ChEBI ID: CHEBI:92209
  CAS Number: 52468-60-7
  DrugBank ID: DB04841
  TTD ID: D05CEU
  VARIDT ID: DR00727
  INTEDE ID: DR0708

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Voltage-gated calcium channel alpha Cav2.1 (CACNA1A)	TTX4QDJ	CAC1A_HUMAN	Inhibitor	[5]
Voltage-gated calcium channel alpha Cav3.2 (CACNA1H)	TTZPWGN	CAC1H_HUMAN	Blocker	[6]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Substrate	[7]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Substrate	[8]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Substrate	[8]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Substrate	[8]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Substrate	[8]

Molecular Expression Atlas of This Drug

• The Studied Disease: Migraine
• ICD Disease Classification: 8A80

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Voltage-gated calcium channel alpha Cav3.2 (CACNA1H)	DTT	CACNA1H	1.31E-04	-0.76	-2.12
Cytochrome P450 2A6 (CYP2A6)	DME	CYP2A6	5.94E-01	-9.00E-02	-4.71E-01
Cytochrome P450 1A2 (CYP1A2)	DME	CYP1A2	1.57E-01	-2.01E-01	-6.73E-01
Cytochrome P450 2D6 (CYP2D6)	DME	CYP2D6	1.02E-01	-3.26E-02	-1.33E-01
Cytochrome P450 1A1 (CYP1A1)	DME	CYP1A1	5.71E-01	-1.43E-01	-5.46E-01
Cytochrome P450 2C9 (CYP2C9)	DME	CYP2C9	2.69E-01	6.97E-02	1.48E-01

References

• [1] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 012102.
• [2] BDDCS applied to over 900 drugs
• [3] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [4] 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
• [5] Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.
• [6] Positive allosteric interaction of structurally diverse T-type calcium channel antagonists. Cell Biochem Biophys. 2009;55(2):81-93.
• [7] 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.
• [8] Oxidative metabolism of flunarizine and cinnarizine by microsomes from B-lymphoblastoid cell lines expressing human cytochrome P450 enzymes. Biol Pharm Bull. 1996 Nov;19(11):1511-4.