A small-molecule inhibitor of integrin α2β1 introduces a new strategy for antithrombotic therapy

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
Issue: 2010: 103/2 (Feb) pp. 251–479
Pages: 387-397

A small-molecule inhibitor of integrin α2β1 introduces a new strategy for antithrombotic therapy

L. Nissinen (1), O. T. Pentikäinen (2), A. Jouppila (3), J. Käpylä (4), M. Ojala (1), J. Nieminen (1), A. Lipsanen (5), H. Lappalainen (5), B. Eckes (6), M. S. Johnson (7), R. Lassila (3), A. Marjamäki (1), J. Heino (4)

(1) Biotie Therapies Corp., Turku, Finland; (2) Nanoscience Center, Department of Biological and Environmental Science, University of Jyväskylä, Finland; (3) Clinical Research Institute,Helsinki University Central Hospital, Finland; (4) Department of Biochemistry, University of Turku, Finland; (5) CNServices, Kuopio, Finland; (6) Department of Dermatology, University of Cologne, Germany; (7) Department of Biochemistry and Pharmacy, Åbo Akademi University,Turku, Finland


integrin, collagen, Platelet, antithrombotic therapy


Interaction of blood platelets with vascular collagen is an initiating event in haemostasis and thrombus formation. Based on molecular modelling of human integrin α2I domain and cell-based screening assays we have developed sulfonamide derivatives, a mechanistically novel class of molecules. These molecules show antiplatelet efficacy by selectively inhibiting α2β1 integrin-mediated collagen binding. One sulfonamide derivative, named BTT-3016, showed inhibitory capacity in several assessments of human platelet interaction with collagen. It inhibited about 90% of the aggregation of gel-filtered magnesium-supplemented platelets and 70% of aggregation in PPACK-anticoagulated platelet-rich plasma when stimulated with collagen but not with ADP. The antiplatelet activity of BTT-3016 was dependent on α2β1 integrin, since in collagen binding test BTT-3016 had no effect on the platelets derived from α2 integrin null mice. When tested in an in vivo model in mice, BTT-3016 clearly reduced thrombus formation on the vessel wall after vascular injury. Furthermore, BTT-3016 prolonged tail-bleeding time in a manner comparable to aspirin. We show that new α2β1 inhibitors exert collagen-specific antiplatelet activity and regulate thrombus growth in vivo without compromising primary haemostasis more than aspirin. We suggest that the α2β1 inhibiting strategy could be further developed for the prevention and treatment of arterial thrombosis.

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