A1 Refereed original research article in a scientific journal
A small-molecule inhibitor of integrin alpha 2 beta 1 introduces a new strategy for antithrombotic therapy
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
Publisher: SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN
Publication year: 2010
Journal: Thrombosis and Haemostasis
Journal name in source: THROMBOSIS AND HAEMOSTASIS
Journal acronym: THROMB HAEMOSTASIS
Number in series: 2
Volume: 103
Issue: 2
First page : 387
Last page: 397
Number of pages: 11
ISSN: 0340-6245
DOI: https://doi.org/10.1160/TH09-06-0358(external)
Abstract
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.
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.
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