Discovery and antiplatelet activity of a selective PI3Kβ inhibitor (MIPS-9922)

A series of amino-substituted triazines were developed and examined for PI3K13 inhibition and anti platelet function. Structural adaptations of a morpholine ring of the prototype pan-PI3K inhibitor ZSTK474 yielded PI3K beta selective compounds, where the selectivity largely derives from an interaction with the non-conserved Asp862 residue, as shown by site directed mutagenesis. The most PI3K beta selective inhibitor from the series was studied in detail through a series of in vitro and in vivo functional studies. MIPS-9922, 10 potently inhibited ADP-induced washed platelet aggregation. It also inhibited integrin alpha(IIb)beta(3) activation and alpha(IIb)beta(3) dependent platelet adhesion to immobilized vWF under high shear. It prevented arterial thrombus formation in the in vivo electrolytic mouse model of thrombosis without inducing prolonged bleeding or excess blood loss. (C) 2016 Elsevier Masson SAS. All rights reserved.