UK-396,082


Synonyms	UK 396082 UK-396082 Uk-396,082
Status
Molecule Category	UNKNOWN
UNII	2Q5861SUIG
EPA CompTox	DTXSID70193074


Active Pharmaceutical Ingredients Bioactive chemicals	Exact Similarity SubStructure	Threshold (%) >= 70

Structure


InChI Key	OTDGPKRCQXSTPV-JTQLQIEISA-N
Smiles	CCCn1cnc(C[C@H](CCCN)C(=O)O)c1
InChI	InChI=1S/C12H21N3O2/c1-2-6-15-8-11(14-9-15)7-10(12(16)17)4-3-5-13/h8-10H,2-7,13H2,1H3,(H,16,17)/t10-/m0/s1

Physicochemical Descriptors

Property Name	Value
Molecular Formula	C12H21N3O2
Molecular Weight	239.32
AlogP	1.28
Hydrogen Bond Acceptor	4.0
Hydrogen Bond Donor	2.0
Number of Rotational Bond	8.0
Polar Surface Area	81.14
Molecular species	ZWITTERION
Aromatic Rings	1.0
Heavy Atoms	17.0

Reference

Journal : J. Med. Chem.

Title : Discovery of potent & selective inhibitors of activated thrombin-activatable fibrinolysis inhibitor for the treatment of thrombosis.

PubMed ID : 17990866

DOI : 10.1021/jm0702433

Year : 2007

Volume : 50

Issue : 24

First Page : 6095

Last Page : 6103

Authors : Bunnage ME, Blagg J, Steele J, Owen DR, Allerton C, McElroy AB, Miller D, Ringer T, Butcher K, Beaumont K, Evans K, Gray AJ, Holland SJ, Feeder N, Moore RS, Brown DG.

Abstract : Thrombin-activatable fibrinolysis inhibitor (TAFI) has emerged as a key link between the coagulation and fibrinolysis cascades and represents a promising new target for the treatment of thrombosis. A novel series of imidazolepropionic acids has been designed that exhibit high potency against activated TAFI (TAFIa) and excellent selectivity over plasma carboxypeptidase N (CPN). Structure activity relationships suggest that the imidazole moiety plays a key role in binding to the catalytic zinc of TAFIa, and this has been supported by crystallographic studies using porcine pancreatic carboxypeptidase B as a surrogate for TAFIa. The SAR program led to the identification of 21 (TAFIa Ki = 10 nM, selectivity TAFIa/CPN > 1000) as a candidate for clinical development. Compound 21 exhibited antithrombotic efficacy in a rabbit model of venous thrombosis, yet had no effect on surgical bleeding in the rabbit. In addition, 21 exhibited an excellent preclinical and clinical pharmacokinetic profile, characterized by paracellular absorption, low clearance, and a low volume of distribution, fully consistent with its physicochemical properties of low molecular weight (MW = 239) and high hydrophilicity (log D = -2.8). These data indicate 21 (UK-396,082) has potential as a novel TAFIa inhibitor for the treatment of thrombosis and other fibrin-dependent diseases in humans.

Reference

Journal : J. Med. Chem.

Title : Discovery of potent & selective inhibitors of activated thrombin-activatable fibrinolysis inhibitor for the treatment of thrombosis.

PubMed ID : 17990866

DOI : 10.1021/jm0702433

Year : 2007

Volume : 50

Issue : 24

First Page : 6095

Last Page : 6103

Authors : Bunnage ME, Blagg J, Steele J, Owen DR, Allerton C, McElroy AB, Miller D, Ringer T, Butcher K, Beaumont K, Evans K, Gray AJ, Holland SJ, Feeder N, Moore RS, Brown DG.

Reference

Journal : J. Med. Chem.

Title : Discovery of potent & selective inhibitors of activated thrombin-activatable fibrinolysis inhibitor for the treatment of thrombosis.

PubMed ID : 17990866

DOI : 10.1021/jm0702433

Year : 2007

Volume : 50

Issue : 24

First Page : 6095

Last Page : 6103

Authors : Bunnage ME, Blagg J, Steele J, Owen DR, Allerton C, McElroy AB, Miller D, Ringer T, Butcher K, Beaumont K, Evans K, Gray AJ, Holland SJ, Feeder N, Moore RS, Brown DG.

Reference

Journal : J. Med. Chem.

Title : Discovery of potent & selective inhibitors of activated thrombin-activatable fibrinolysis inhibitor for the treatment of thrombosis.

PubMed ID : 17990866

DOI : 10.1021/jm0702433

Year : 2007

Volume : 50

Issue : 24

First Page : 6095

Last Page : 6103

Authors : Bunnage ME, Blagg J, Steele J, Owen DR, Allerton C, McElroy AB, Miller D, Ringer T, Butcher K, Beaumont K, Evans K, Gray AJ, Holland SJ, Feeder N, Moore RS, Brown DG.

Reference

Journal : Bioorg. Med. Chem. Lett.

Title : Oxygenated analogues of UK-396082 as inhibitors of activated thrombin activatable fibrinolysis inhibitor.

PubMed ID : 19954973

DOI : 10.1016/j.bmcl.2009.11.029

Year : 2010

Volume : 20

Issue : 1

First Page : 92

Last Page : 96

Authors : Owen DR, Bull DJ, Bunnage ME, Glossop MS, Maguire RJ, Strang RS.

Abstract : A suitable inhibitor of activated thrombin activatable fibrinolysis inhibitor (TAFIa) has the potential to be a novel treatment for thrombosis. The TAFIa inhibitor UK-396082 (1) was used as a starting point to seek more potent analogues. With knowledge of encouraging human pharmacokinetics and toleration for the clinical candidate (1), the programme continued to seek structure-activity relationships (SAR) that could positively impact on both potency and half-life, and therefore the projected dose of any future nominated clinical agent. A series of oxygenated analogues based on compound 1 were prepared to evaluate changes in pharmacology, selectivity and pharmacokinetics.

Reference

Journal : Bioorg. Med. Chem. Lett.

Title : Oxygenated analogues of UK-396082 as inhibitors of activated thrombin activatable fibrinolysis inhibitor.

PubMed ID : 19954973

DOI : 10.1016/j.bmcl.2009.11.029

Year : 2010

Volume : 20

Issue : 1

First Page : 92

Last Page : 96

Authors : Owen DR, Bull DJ, Bunnage ME, Glossop MS, Maguire RJ, Strang RS.

Reference

Journal : Bioorg. Med. Chem.

Title : Design and synthesis of conformationally restricted inhibitors of active thrombin activatable fibrinolysis inhibitor (TAFIa).

PubMed ID : 24588961

DOI : 10.1016/j.bmc.2014.02.010

Year : 2014

Volume : 22

Issue : 7

First Page : 2261

Last Page : 2268

Authors : Brink M, Dahlén A, Olsson T, Polla M, Svensson T.

Abstract : A series of 4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid and 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylic acid derivatives designed as inhibitors of TAFIa has been prepared via a common hydrogenation-alkylation sequence starting from the appropriate benzimidazole and imidazopyridine system. We present a successful design strategy using a conformational restriction approach resulting in potent and selective inhibitors of TAFIa. The X-ray structure of compound 5 in complex with a H333Y/H335Q double mutant TAFI indicate that the conformational restriction is responsible for the observed potency increase.

Assay Description	Organism	Bioactivity
Inhibition of porcine pancreatic carboxypeptidase B	Sus scrofa	206.0 nM
Inhibition of human TAFIa	Homo sapiens	10.0 nM
Antithrombotic efficacy in anesthetized rabbit assessed as inhibition of thrombus formation at 800 nM relative to control	Oryctolagus cuniculus	36.0 %
Inhibition of thrombus weight in iv dosed anesthetized rabbit at 80 nM relative to control	Oryctolagus cuniculus	37.0 %
Inhibition of active form of human recombinant TAFI assessed as substrate turnover every 15 seconds for 30 mins	Homo sapiens	16.0 nM
Inhibition of human pancreatic carboxypeptidase B	Homo sapiens	206.0 nM
Inhibition of human TAF1a using hippuryl-L-arginine/hippuryl-L-lysine as substrate by liquid chromatographic analysis	Homo sapiens	450.0 nM

Cross References

Resources	Reference
ChEMBL	CHEMBL398110
DrugBank	DB12099
FDA SRS	2Q5861SUIG
Guide to Pharmacology	8657
PDB	720
PubChem	11241908
SureChEMBL	SCHEMBL3841442
ZINC	ZINC000001910640

CONTENTS

Structure
Chemical and Physical Properties