Details of the Drug

General Information of Drug (ID: DMY9TCW)

• Drug Name: Bromazepam
• Synonyms: Bromazepamum; Calmepam; Compedium; Compendium; Creosedin; Durazanil; Lectopam; Lekotam; Lexaurin; Lexilium; Lexomil; Lexotan; Lexotanil; Normoc; Somalium; Ultramidol; Bromazepamum [Latin]; LA Xvii; KL 001; Ro 53350; Apo-Bromazepam; Brazepam (TN); Bromaze (TN); Bromazepam(USAN; Bromazepamum [INN-Latin]; Gen-Bromazepam; KL-001; Lectopam (TN); Lexotan (TN); Novo-bromazepam; Nu-Bromazepam; Ro 4-9253; Ro 5-3350; Bromazepam (JP15/USAN/INN); Bromazepam [USAN:INN:BAN:JAN]; 1,3-Dihydro-7-bromo-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one; 7-Bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzdiazepin-2-one; 7-Bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one; 7-Bromo-5-(2-pyridyl)-3H-1,4-benzodiaxepin-2(1H)-one; 7-Bromo-5-(2-pyridyl)-3H-1,4-benzodiazepin-2(1H)-one; 7-bromo-5-pyridin-2-yl-1,3-dihydro-1,4-benzodiazepin-2-one

Indication

Disease Entry	ICD 11	Status	REF
Anxiety disorder	6B00-6B0Z	Approved	[1]
Panic attacks	MB23.H	Approved	[1]

• Therapeutic Class: Hypnotics and Sedatives
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 316.15
  Topological Polar Surface Area (xlogp); 1.7
  Rotatable Bond Count (rotbonds); 1
  Hydrogen Bond Donor Count (hbonddonor); 1
  Hydrogen Bond Acceptor Count (hbondacc); 3
• ADMET Property:
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 1: high solubility and high permeability [2]
  Bioavailability: 84% of drug becomes completely available to its intended biological destination(s) [3]
  Clearance: The clearance of drug is 0.82 mL/min/kg [4]
  Half-life: The concentration or amount of drug in body reduced by one-half in 10 - 20 hours [5]
  Metabolism: The drug is metabolized via the hepatic [6]
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 1.3556 micromolar/kg/day [7]
  Unbound Fraction: The unbound fraction of drug in plasma is 0.48% [5]
  Vd: The volume of distribution (Vd) of drug is 1.56 L/kg [4]
  Water Solubility: The ability of drug to dissolve in water is measured as 0.17 mg/mL [2]
• Chemical Identifiers:
  Formula: C14H10BrN3O
  IUPAC Name: 7-bromo-5-pyridin-2-yl-1,3-dihydro-1,4-benzodiazepin-2-one
  Canonical SMILES: C1C(=O)NC2=C(C=C(C=C2)Br)C(=N1)C3=CC=CC=N3
  InChI: InChI=1S/C14H10BrN3O/c15-9-4-5-11-10(7-9)14(17-8-13(19)18-11)12-3-1-2-6-16-12/h1-7H,8H2,(H,18,19)
  InChIKey: VMIYHDSEFNYJSL-UHFFFAOYSA-N
• Cross-matching ID:
  PubChem CID: 2441
  ChEBI ID: CHEBI:31302
  CAS Number: 1812-30-2
  DrugBank ID: DB01558
  TTD ID: D0E3FD
  INTEDE ID: DR0231

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Glutamate receptor AMPA (GRIA)	TTAN6JD	NOUNIPROTAC	Binder	[8]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Substrate	[9]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Substrate	[9]

Molecular Expression Atlas of This Drug

• The Studied Disease: Anxiety disorder
• ICD Disease Classification: 6B00-6B0Z

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Glutamate receptor AMPA (GRIA)	DTT	NO-GeName	1.79E-04	-0.69	-0.58
Cytochrome P450 1A2 (CYP1A2)	DME	CYP1A2	7.36E-01	1.62E-02	1.08E-01
Mephenytoin 4-hydroxylase (CYP2C19)	DME	CYP2C19	2.40E-01	-3.31E-02	-1.97E-01

References

• [1] Drug information of Bromazepam, 2008. eduDrugs.
• [2] BDDCS applied to over 900 drugs
• [3] Critical Evaluation of Human Oral Bioavailability for Pharmaceutical Drugs by Using Various Cheminformatics Approaches
• [4] An FDA phase I clinical trial of quinacrine sterilization (QS). Int J Gynaecol Obstet. 2003 Oct;83 Suppl 2:S45-9.
• [5] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [6] 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.
• [7] 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
• [8] Glutamatergic and GABAergic modulations of ultrasonic vocalizations during maternal separation distress in mouse pups. Psychopharmacology (Berl). 2009 May;204(1):61-71.
• [9] Selective serotonin reuptake inhibitors and CNS drug interactions. A critical review of the evidence. Clin Pharmacokinet. 1997 Dec;33(6):454-71.
• [10] Roles of cytochromes P450 1A2, 2A6, and 2C8 in 5-fluorouracil formation from tegafur, an anticancer prodrug, in human liver microsomes. Drug Metab Dispos. 2000 Dec;28(12):1457-63.
• [11] Effects of polyunsaturated fatty acids on prostaglandin synthesis and cyclooxygenase-mediated DNA adduct formation by heterocyclic aromatic amines in human adenocarcinoma colon cells. Mol Carcinog. 2004 Jul;40(3):180-8.
• [12] Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase 2A1 (hSULT2A1). Drug Metab Dispos. 2014 Nov;42(11):1843-50.
• [13] Cytochrome P450 1A2 (CYP1A2) activity and risk factors for breast cancer: a cross-sectional study. Breast Cancer Res. 2004;6(4):R352-65.
• [14] PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genomics. 2015 Aug;25(8):416-26.
• [15] The effect of apigenin on pharmacokinetics of imatinib and its metabolite N-desmethyl imatinib in rats. Biomed Res Int. 2013;2013:789184.
• [16] Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
• [17] The influence of metabolic gene polymorphisms on urinary 1-hydroxypyrene concentrations in Chinese coke oven workers. Sci Total Environ. 2007 Aug 1;381(1-3):38-46.
• [18] Identification of P450 enzymes involved in metabolism of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1993 Sep;348(3):332-7.
• [19] Metabolism and metabolic inhibition of xanthotoxol in human liver microsomes. Evid Based Complement Alternat Med. 2016;2016:5416509.
• [20] High-dose rabeprazole/amoxicillin therapy as the second-line regimen after failure to eradicate H. pylori by triple therapy with the usual doses of a proton pump inhibitor, clarithromycin and amoxicillin. Hepatogastroenterology. 2003 Nov-Dec;50(54):2274-8.
• [21] 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.
• [22] Cytochrome P450 pharmacogenetics and cancer. Oncogene. 2006 Mar 13;25(11):1679-91.
• [23] CYP2C19*17 is associated with decreased breast cancer risk. Breast Cancer Res Treat. 2009 May;115(2):391-6.
• [24] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [25] Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1995 Dec;353(1):116-21.
• [26] Diclofenac and its derivatives as tools for studying human cytochromes P450 active sites: particular efficiency and regioselectivity of P450 2Cs. Biochemistry. 1999 Oct 26;38(43):14264-70.
• [27] A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother. 1998 May;32(5):554-63.
• [28] Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001 Feb;120(2):525-33.
• [29] Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol. Br J Anaesth. 1998 Jun;80(6):788-95.
• [30] Reduced inhibition of cortical glutamate and GABA release by halothane in mice lacking the K+ channel, TREK-1. Br J Pharmacol. 2007 Nov;152(6):939-45.
• [31] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [32] Eszopiclone: its use in the treatment of insomnia. Neuropsychiatr Dis Treat. 2007 Aug;3(4):441-453.
• [33] Effects of sevoflurane on carrageenan- and fentanyl-induced pain hypersensitivity in Sprague-Dawley rats. Can J Anaesth. 2009 Feb;56(2):126-35.
• [34] Enflurane directly depresses glutamate AMPA and NMDA currents in mouse spinal cord motor neurons independent of actions on GABAA or glycine receptors. Anesthesiology. 2000 Oct;93(4):1075-84.
• [35] Transmembrane residues define the action of isoflurane at the GABAA receptor alpha-3 subunit. Brain Res. 2005 Jan 25;1032(1-2):30-5.
• [36] GABA(A) receptor ligands and their therapeutic potentials. Curr Top Med Chem. 2002 Aug;2(8):817-32.
• [37] Pharmacologic management of Alzheimer disease, Part II: Antioxidants, antihypertensives, and ergoloid derivatives. Ann Pharmacother. 1999 Feb;33(2):188-97.
• [38] Anaesthetic drugs: linking molecular actions to clinical effects. Curr Pharm Des. 2006;12(28):3665-79.
• [39] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015