Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTP18AY)

• DTT Name: Carboxypeptidase B2 (CPB2)
• Synonyms: Thrombin-activable fibrinolysis inhibitor; TAFI; Plasma carboxypeptidase B; Carboxypeptidase U; CPU; CPB2
• Gene Name: CPB2
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Peptidase
• UniProt ID: CBPB2_HUMAN
• TTD ID: T98022
• EC Number: EC 3.4.17.20
• Sequence:
  MKLCSLAVLVPIVLFCEQHVFAFQSGQVLAALPRTSRQVQVLQNLTTTYEIVLWQPVTAD
  LIVKKKQVHFFVNASDVDNVKAHLNVSGIPCSVLLADVEDLIQQQISNDTVSPRASASYY
  EQYHSLNEIYSWIEFITERHPDMLTKIHIGSSFEKYPLYVLKVSGKEQAAKNAIWIDCGI
  HAREWISPAFCLWFIGHITQFYGIIGQYTNLLRLVDFYVMPVVNVDGYDYSWKKNRMWRK
  NRSFYANNHCIGTDLNRNFASKHWCEEGASSSSCSETYCGLYPESEPEVKAVASFLRRNI
  NQIKAYISMHSYSQHIVFPYSYTRSKSKDHEELSLVASEAVRAIEKISKNTRYTHGHGSE
  TLYLAPGGGDDWIYDLGIKYSFTIELRDTGTYGFLLPERYIKPTCREAFAAVSKIAWHVI
  RNV
• Function: Cleaves C-terminal arginine or lysine residues from biologically active peptides such as kinins or anaphylatoxins in the circulation thereby regulating their activities. Down- regulates fibrinolysis by removing C-terminal lysine residues from fibrin that has already been partially degraded by plasmin.
• KEGG Pathway:
  Complement and coagulation cascades (hsa04610)
  Pancreatic secretion (hsa04972)
  Protein digestion and absorption (hsa04974)
• Reactome Pathway: Metabolism of Angiotensinogen to Angiotensins (R-HSA-2022377)

Molecular Interaction Atlas (MIA) of This DTT

4 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
DS-1040	DMXCN37	Ischemic stroke	8B11.5Z	Phase 1	[2]
SAR-104772	DMQ9ZY0	Cerebrovascular ischaemia	8B1Z	Phase 1	[3]
SAR-126119	DMKHM7O	Cerebrovascular ischaemia	8B1Z	Phase 1	[1]
UK-396082	DMFYKDX	Thrombosis	DB61-GB90	Phase 1	[4]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AZD-9684	DMHA5ME	Thrombosis	DB61-GB90	Discontinued in Phase 2	[5]

13 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(+/-)-5-amino-2-(mercaptomethyl)pentanoic acid	DMSNWA6	Discovery agent	N.A.	Investigative	[6]
2-(3-aminophenyl)-3-mercaptopropanoic acid	DMQB9SC	Discovery agent	N.A.	Investigative	[7]
2-(3-guanidinophenyl)-3-mercaptopropanoic acid	DMZX2GE	Discovery agent	N.A.	Investigative	[7]
2-(4-benzoylpiperidine-1-carbonyl)benzoic acid	DMGMZV9	Discovery agent	N.A.	Investigative	[8]
3-mercapto-2-(piperidin-3-yl)propanoic acid	DMPJBNC	Discovery agent	N.A.	Investigative	[7]
3-mercapto-2-(piperidin-4-yl)propanoic acid	DMYQG7A	Discovery agent	N.A.	Investigative	[7]
6-Amino-2-(1H-imidazol-4-yl)-hexanoic acid	DMMUE05	Discovery agent	N.A.	Investigative	[9]
DL-benzylsuccinic acid	DMHI9ZJ	Discovery agent	N.A.	Investigative	[8]
DL-guanidinoethylmercaptosuccinic acid	DMM1GXI	Discovery agent	N.A.	Investigative	[8]
MN-462	DM1XY5F	Thrombosis	DB61-GB90	Investigative	[10]
PMID14640538C3	DMR2L6X	Discovery agent	N.A.	Investigative	[11]
PMID19954973C4	DMDYZE5	Discovery agent	N.A.	Investigative	[4]
SQ-24798	DMW7Y9L	Discovery agent	N.A.	Investigative	[7]

References

• [1] TAFIa inhibitors in the treatment of thrombosis. Curr Opin Drug Discov Devel. 2008 Jul;11(4):480-6.
• [2] Clinical pipeline report, company report or official report of Daiichi Sankyo.
• [3] Carboxypeptidase U (TAFIa): a new drug target for fibrinolytic therapy . Journal of Thrombosis and Haemostasis Volume 7, Issue 12, pages 1962-1971, December 2009.
• [4] Oxygenated analogues of UK-396082 as inhibitors of activated thrombin activatable fibrinolysis inhibitor. Bioorg Med Chem Lett. 2010 Jan 1;20(1):92-6.
• [5] Clinical pipeline report, company report or official report of AstraZeneca.
• [6] Discovery of potent & selective inhibitors of activated thrombin-activatable fibrinolysis inhibitor for the treatment of thrombosis. J Med Chem. 2007 Nov 29;50(24):6095-103.
• [7] 3-Mercaptopropionic acids as efficacious inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa). Bioorg Med Chem Lett. 2007 Mar 1;17(5):1349-54.
• [8] A new type of five-membered heterocyclic inhibitors of basic metallocarboxypeptidases. Eur J Med Chem. 2009 Aug;44(8):3266-71.
• [9] Imidazole acetic acid TAFIa inhibitors: SAR studies centered around the basic P(1)(') group. Bioorg Med Chem Lett. 2004 May 3;14(9):2141-5.
• [10] 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: 1594).
• [11] Synthesis and evaluation of imidazole acetic acid inhibitors of activated thrombin-activatable fibrinolysis inhibitor as novel antithrombotics. J Med Chem. 2003 Dec 4;46(25):5294-7.