23980-96-3Relevant academic research and scientific papers
Creating novel activated factor XI inhibitors through fragment based lead generation and structure aided drug design
Fjellstr?m, Ola,Akkaya, Sibel,Beisel, Hans-Georg,Eriksson, Per-Olof,Erixon, Karl,Gustafsson, David,Jurva, Ulrik,Kang, Daiwu,Karis, David,Knecht, Wolfgang,Nerme, Viveca,Nilsson, Ingemar,Olsson, Thomas,Redzic, Alma,Roth, Robert,Sandmark, Jenny,Tigerstr?m, Anna,?ster, Linda
, (2015/02/19)
Activated factor XI (FXIa) inhibitors are anticipated to combine anticoagulant and profibrinolytic effects with a low bleeding risk. This motivated a structure aided fragment based lead generation campaign to create novel FXIa inhibitor leads. A virtual screen, based on docking experiments, was performed to generate a FXIa targeted fragment library for an NMR screen that resulted in the identification of fragments binding in the FXIa S1 binding pocket. The neutral 6-chloro-3,4-dihydro-1H-quinolin-2-one and the weakly basic quinolin-2-amine structures are novel FXIa P1 fragments. The expansion of these fragments towards the FXIa prime side binding sites was aided by solving the X-ray structures of reported FXIa inhibitors that we found to bind in the S1-S1'-S2' FXIa binding pockets. Combining the X-ray structure information from the identified S1 binding 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment and the S1-S1'-S2' binding reference compounds enabled structure guided linking and expansion work to achieve one of the most potent and selective FXIa inhibitors reported to date, compound 13, with a FXIa IC50 of 1.0 nM. The hydrophilicity and large polar surface area of the potent S1-S1'-S2' binding FXIa inhibitors compromised permeability. Initial work to expand the 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment towards the prime side to yield molecules with less hydrophilicity shows promise to afford potent, selective and orally bioavailable compounds.
