title: The role of structural information in the discovery of direct thrombin and factor Xa inhibitors.
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.
authors.affiliation: Structural Research Group, Department of Lead Identification and Optimization Support, Boehringer-Ingelheim Pharma GmbH & Co. KG, Birkendorferstrasse 65, 88397 Biberach an der Riss, Germany. herbert.nar@boehringer-ingelheim.com
authors.forename: Herbert
authors.initials: H
authors.lastname: Nar
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000737:chemistry*; D019774:Blood Coagulation Factor Inhibitors / Q000737:chemistry*; D015195:Drug Design; D015951:Factor Xa / Q000737:chemistry*; D065427:Factor Xa Inhibitors; D006801:Humans; D011487:Protein Conformation; D011516:Prothrombin / Q000037:antagonists & inhibitors / Q000737:chemistry; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D000991:Antithrombins; D019774:Blood Coagulation Factor Inhibitors; D065427:Factor Xa Inhibitors; D011516:Prothrombin; C025337:Factor IIa; D013917:Thrombin; D015951:Factor Xa