Details of the Drug

General Information of Drug (ID: DMTE071)

• Drug Name: CHF-5074
• Synonyms: CHF 5074; CHF5074; 749269-83-8; CHF-5074; Itanapraced; UNII-C35RF1MWQZ; GHF-5074; C35RF1MWQZ; CHEMBL196945; 1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid; 1-[4-(3,4-dichlorophenyl)-3-fluorophenyl]cyclopropane-1-carboxylic acid; 1-(3',4'-Dichloro-2-Fluorobiphenyl-4-Yl)cyclopropanecarboxylic Acid; H50; SCHEMBL407631; GTPL7339; DTXSID30225901; AOB5325; LIYLTQQDABRNRX-UHFFFAOYSA-N; ZINC3986651; EX-A1963; BDBM50172482; AKOS026750398; SB16945; CS-5022; NCGC00408905-01; AS-16850; HY-14399; BC600569; FT-0708261

Indication

Disease Entry	ICD 11	Status	REF
Alzheimer disease	8A20	Phase 2	[1], [2]
Cognitive impairment	6D71	Phase 2	[3], [4]

• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 325.2
  Topological Polar Surface Area (xlogp); 4.7
  Rotatable Bond Count (rotbonds); 3
  Hydrogen Bond Donor Count (hbonddonor); 1
  Hydrogen Bond Acceptor Count (hbondacc); 3
• Chemical Identifiers:
  Formula: C16H11Cl2FO2
  IUPAC Name: 1-[4-(3,4-dichlorophenyl)-3-fluorophenyl]cyclopropane-1-carboxylic acid
  Canonical SMILES: C1CC1(C2=CC(=C(C=C2)C3=CC(=C(C=C3)Cl)Cl)F)C(=O)O
  InChI: InChI=1S/C16H11Cl2FO2/c17-12-4-1-9(7-13(12)18)11-3-2-10(8-14(11)19)16(5-6-16)15(20)21/h1-4,7-8H,5-6H2,(H,20,21)
  InChIKey: LIYLTQQDABRNRX-UHFFFAOYSA-N
• Cross-matching ID:
  PubChem CID: 9996409
  CAS Number: 749269-83-8
  TTD ID: D03MFQ

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Gamma-secretase (GS)	TT9W8GU	APH1A_HUMAN; APH1B_HUMAN; PEN2_HUMAN; NICA_HUMAN; PSN1_HUMAN	Modulator	[5]

Molecular Expression Atlas of This Drug

• The Studied Disease: Alzheimer disease
• ICD Disease Classification: 8A20

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Gamma-secretase (GS)	DTT	APH1A; APH1B; NCSTN; PSENEN; PSEN1	1.47E-02	-0.09	-0.37

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: 7339).
• [2] ClinicalTrials.gov (NCT01303744) Evaluation of Safety & Tolerability of Multiple Dose Regimens of CHF 5074 and Exploration of Effects on Potential Markers of Clinical Efficacy in Patients With Mild Cognitive Impairment. U.S. National Institutes of Health.
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] CHF5074, a novel gamma-secretase modulator, attenuates brain beta-amyloid pathology and learning deficit in a mouse model of Alzheimer's disease.Br J Pharmacol.2009 Mar;156(6):982-93.
• [6] The geminal dimethyl analogue of Flurbiprofen as a novel Abeta42 inhibitor and potential Alzheimer's disease modifying agent. Bioorg Med Chem Lett. 2006 Apr 15;16(8):2219-23.
• [7] Clinical pipeline report, company report or official report of Roche (2009).
• [8] A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013 Jul 25;369(4):341-50.
• [9] Pharmacodynamics and pharmacokinetics of the gamma-secretase inhibitor PF-3084014.J Pharmacol Exp Ther.2010 Jul;334(1):269-77.
• [10] Determination of the gamma-secretase inhibitor MK-0752 in human plasma by online extraction and electrospray tandem mass spectrometry (HTLC-ESI-MS/MS). J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Sep 1;878(25):2348-52.
• [11] Safety and tolerability of the gamma-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol. 2012 Nov;69(11):1430-40.
• [12] Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors. J Clin Oncol. 2012 Jul 1;30(19):2348-53.
• [13] Clinical pipeline report, company report or official report of Ayala Pharmaceuticals.
• [14] Modulation of gamma-secretase for the treatment of Alzheimer's disease. Int J Alzheimers Dis. 2012;2012:210756.