A1 Journal article – refereed
A small-molecule inhibitor of integrin alpha 2 beta 1 introduces a new strategy for antithrombotic therapy

List of Authors: Nissinen L, Pentikainen OT, Jouppila A, Kapyla J, Ojala M, Nieminen J, Lipsanen A, Lappalainen H, Eckes B, Johnson MS, Lassila R, Marjamaki A, Heino J
Publication year: 2010
Journal: Thrombosis and Haemostasis
Journal name in source: THROMBOSIS AND HAEMOSTASIS
Number in series: 2
Volume number: 103
Issue number: 2
Number of pages: 11
ISSN: 0340-6245

Interaction of blood platelets with vascular collagen is an initiating event in haemostasis and thrombus formation. Based on molecular modelling of human integrin alpha 21 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 alpha 2 beta 1 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 AN The antiplatelet activity of BTT-3016 was dependent on alpha 2 beta 1 integrin, since in Collagen binding test BTT-3016 had no effect on the platelets derived from alpha 2 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 alpha 2 beta 1 inhibitors exert collagen-specific antiplatelet activity and regulate thrombus growth in vivo without compromising primary haemostasis more than aspirin. We suggest that the alpha 2 beta 1 inhibiting strategy could be further developed for the prevention and treatment of arterial thrombosis.

Last updated on 2019-21-08 at 21:24