Details of the Drug

General Information of Drug (ID: DMPK34E)

• Drug Name: Sun13834
• Synonyms: Trifluperidol; Trisedil; Triperidol; Psychoperidol; Flumoperone; Psicoperidol; Trisedyl; Psicoperidol-R; McN-JR-2498; 749-13-3; Trifluperidolo; Trifluperidolo [DCIT]; R-2498; Trifluperidolo [Italian]; Trifluperidolum [INN-Latin]; NSC 170978; UNII-R8869Q7R8I; Trifluperidol [USAN:INN:BAN]; P 459; BRN 1556208; CHEMBL15023; 1-Butanone, 1-(4-fluorophenyl)-4-(4-hydroxy-4-(3-(trifluoromethyl)phenyl)-1-piperidinyl)-; GPMXUUPHFNMNDH-UHFFFAOYSA-N; R8869Q7R8I; NSC170978; Triperidol (TN)

Indication

Disease Entry	ICD 11	Status	REF
Gram-positive bacterial infection	1B74-1G40	Phase 2	[1]

• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 409.4
  Topological Polar Surface Area (xlogp); 3.5
  Rotatable Bond Count (rotbonds); 6
  Hydrogen Bond Donor Count (hbonddonor); 1
  Hydrogen Bond Acceptor Count (hbondacc); 7
• Chemical Identifiers:
  Formula: C22H23F4NO2
  IUPAC Name: 1-(4-fluorophenyl)-4-[4-hydroxy-4-[3-(trifluoromethyl)phenyl]piperidin-1-yl]butan-1-one
  Canonical SMILES: C1CN(CCC1(C2=CC(=CC=C2)C(F)(F)F)O)CCCC(=O)C3=CC=C(C=C3)F
  InChI: InChI=1S/C22H23F4NO2/c23-19-8-6-16(7-9-19)20(28)5-2-12-27-13-10-21(29,11-14-27)17-3-1-4-18(15-17)22(24,25)26/h1,3-4,6-9,15,29H,2,5,10-14H2
  InChIKey: GPMXUUPHFNMNDH-UHFFFAOYSA-N
• Cross-matching ID:
  PubChem CID: 5567
  ChEBI ID: CHEBI:135662
  CAS Number: 749-13-3
  TTD ID: D0I8FV
  INTEDE ID: DR1642

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Chymase (CYM)	TT8VUE0	CMA1_HUMAN	Modulator	[2]
Phosphodiesterase 4 (PDE4)	TTV5CGO	NOUNIPROTAC	Inhibitor	[3]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 2D6 (CYP2D6) Main DME	DECB0K3	CP2D6_HUMAN	Substrate	[4]

Molecular Expression Atlas of This Drug

• The Studied Disease: Gram-positive bacterial infection
• ICD Disease Classification: 1B74-1G40

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Chymase (CYM)	DTT	CMA1	3.36E-05	-0.62	-3.21
Cytochrome P450 2D6 (CYP2D6)	DME	CYP2D6	5.28E-01	-3.69E-02	-1.61E-01
Cytochrome P450 2D6 (CYP2D6)	DME	CYP2D6	9.35E-01	-5.39E-03	-5.20E-02

References

• [1] Emerging drugs for bacterial urinary tract infections. Expert Opin Emerg Drugs. 2005 May;10(2):275-98.
• [2] Oral chymase inhibitor SUN13834 ameliorates skin inflammation as well as pruritus in mouse model for atopic dermatitis.Eur J Pharmacol.2008 Dec 28;601(1-3):186-91.
• [3] Ocular hypotension induced by topical dopaminergic drugs and phosphodiesterase inhibitors. Eur J Pharmacol. 1994 Jun 2;258(1-2):85-94.
• [4] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [5] Inhibitory effects of anticancer drugs on dextromethorphan-O-demethylase activity in human liver microsomes. Cancer Chemother Pharmacol. 1993;32(6):491-5.
• [6] Effect of genetic polymorphism on the metabolism of endogenous neuroactive substances, progesterone and p-tyramine, catalyzed by CYP2D6. Brain Res Mol Brain Res. 2004 Oct 22;129(1-2):117-23.
• [7] CYP2D6 polymorphisms and tamoxifen metabolism: clinical relevance. Curr Oncol Rep. 2010 Jan;12(1):7-15.
• [8] 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.
• [9] 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.
• [10] Inhibition of cytochrome P450 2D6: structure-activity studies using a series of quinidine and quinine analogues. Chem Res Toxicol. 2003 Apr;16(4):450-9.
• [11] Effects of propofol on human hepatic microsomal cytochrome P450 activities. Xenobiotica. 1998 Sep;28(9):845-53.
• [12] Pharmacogenetics of schizophrenia. Am J Med Genet. 2000 Spring;97(1):98-106.
• [13] Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes. Arch Toxicol. 1999 Mar;73(2):65-70.
• [14] Structure-activity relationship for human cytochrome P450 substrates and inhibitors. Drug Metab Rev. 2002 Feb-May;34(1-2):69-82.
• [15] Discovery of potent, selective, orally active, nonpeptide inhibitors of human mast cell chymase. J Med Chem. 2007 Apr 19;50(8):1727-30.
• [16] Immunology of atopic eczema: overcoming the Th1/Th2 paradigm. Allergy. 2013 Aug;68(8):974-82.
• [17] ClinicalTrials.gov (NCT02452515) A Single-blind Pilot Study to Investigate Safety and Tolerability of the Chymase Inhibitor BAY1142524 in Clinically Stable Patients With Left-ventricular Dysfunction.
• [18] Pharmacokinetics, Safety, and Tolerability of the Novel Chymase Inhibitor BAY 1142524 in Healthy Male Volunteers. Clin Pharmacol Drug Dev. 2019 May;8(4):467-479.
• [19] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [20] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [21] 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. (Target id: 2340).
• [22] Therapeutic potential of a specific chymase inhibitor in atopic dermatitis. Jpn J Pharmacol. 2002 Nov;90(3):214-7.
• [23] Identification of 6-substituted 4-arylsulfonyl-1,4-diazepane-2,5-diones as a novel scaffold for human chymase inhibitors. Bioorg Med Chem Lett. 2007 Jun 15;17(12):3431-4.
• [24] Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets. 2007 Mar;6(1):17-26.
• [25] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [26] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [27] Therapeutic targeting of 3',5'-cyclic nucleotide phosphodiesterases: inhibition and beyond. Nat Rev Drug Discov. 2019 Oct;18(10):770-796.
• [28] 2016 FDA drug approvals. Nat Rev Drug Discov. 2017 Feb 2;16(2):73-76.
• [29] Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2006 May;11(2):275-91.
• [30] Trial of Roflumilast Cream for Chronic Plaque Psoriasis. N Engl J Med. 2020 Jul 16;383(3):229-239.
• [31] Antipruritic effect of the topical phosphodiesterase 4 inhibitor E6005 ameliorates skin lesions in a mouse atopic dermatitis model. J Pharmacol Exp Ther. 2013 Jul;346(1):105-12.