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

Bunnage, Mark E., Blagg, Julian, Steele, John, Owen, Dafydd R., Allerton, Charlotte M.N., McElroy, Andrew B., Miller, Duncan, Ringer, Tracy, Butcher, Ken, Beaumont, Kevin C., and others. (2007) Discovery of potent & selective inhibitors of activated thrombin-activatable fibrinolysis inhibitor for the treatment of thrombosis. Journal of Medicinal Chemistry, 50 (24). pp. 6095-6103. ISSN 0022-2623. (doi:10.1021/jm0702433) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided. (Contact us about this Publication)
Official URL
http://dx.doi.org/10.1021/jm0702433

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.

Item Type: Article
DOI/Identification number: 10.1021/jm0702433
Subjects: Q Science > QD Chemistry
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: David Brown
Date Deposited: 11 Jun 2013 13:26 UTC
Last Modified: 29 May 2019 10:17 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/34255 (The current URI for this page, for reference purposes)
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