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  • The role of structural information in the discovery of direct thrombin and factor Xa inhibitors.

The role of structural information in the discovery of direct thrombin and factor Xa inhibitors.

Trends in pharmacological sciences (2012-04-17)
Herbert Nar
ABSTRACT

The quest for novel medications to treat thromboembolic disorders such as venous thrombosis, pulmonary embolism and stroke received a boost when the 3D structures of two major players in the blood coagulation cascade were determined in 1989 and 1993. Structure-guided design of inhibitors of thrombin (factor IIa, fIIa) and factor Xa (fXa) eventually led to the discovery of potent, selective, efficacious, orally active and safe compounds that proved successful in clinical studies. In 2008, the direct thrombin inhibitor dabigatran etexilate developed by Boehringer Ingelheim became the first novel antithrombotic molecular entity to enter the market in 50 years. Additional compounds targeting factor Xa were subsequently granted marketing authorization or are in late-stage clinical studies. In this review, I use selected case studies to describe the discovery of novel fIIa and fXa inhibitors, with a particular emphasis on the pre-eminent role that structural information played in this process.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Thrombin from bovine plasma, ≥60 NIH units/mg protein (biuret)
Sigma-Aldrich
Thrombin from bovine plasma, lyophilized powder, 600-2,000 NIH units/mg protein (biuret)
Sigma-Aldrich
Thrombin from bovine plasma, lyophilized powder, ≥2,000 NIH units/mg protein (E1%/280 = 19.5)
Sigma-Aldrich
Thrombin from bovine plasma, lyophilized powder, 40-300 NIH units/mg protein (biuret)
Sigma-Aldrich
Thrombin from human plasma, 400-1000 NIH units/mg protein
Sigma-Aldrich
Thrombin from human plasma, lyophilized powder, Suitable for routine use in the thrombin time test
Sigma-Aldrich
Thrombin from human plasma, lyophilized powder, ≥2800 NIH units/mg protein (E1%/280, 18.3)
Sigma-Aldrich
Thrombin from human plasma, lyophilized powder, ≥2,000 NIH units/mg protein (E1%/280, 18.3)
Sigma-Aldrich
Thrombin from human plasma, lyophilized powder, 1500-3500 NIH units/mg protein (E1%/280, 18.3), suitable for cell culture
Sigma-Aldrich
Thrombin from human plasma, lyophilized powder, ≥1,000 NIH units/mg protein (E1%/280, 18.3)