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000600501 1001_ $$0P:(DE-HGF)0$$aRoehrig, Susanne$$b0$$eCorresponding author
000600501 245__ $$aDesign and Preclinical Characterization Program toward Asundexian (BAY 2433334), an Oral Factor XIa Inhibitor for the Prevention and Treatment of Thromboembolic Disorders
000600501 260__ $$aWashington, DC$$bACS$$c2023
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000600501 520__ $$aActivated coagulation factor XI (FXIa) is a highly attractive antithrombotic target as it contributes to the development and progression of thrombosis but is thought to play only a minor role in hemostasis so that its inhibition may allow for decoupling of antithrombotic efficacy and bleeding time prolongation. Herein, we report our major efforts to identify an orally bioavailable, reversible FXIa inhibitor. Using a protein structure-based de novo design approach, we identified a novel micromolar hit with attractive physicochemical properties. During lead modification, a critical problem was balancing potency and absorption by focusing on the most important interactions of the lead series with FXIa while simultaneously seeking to improve metabolic stability and the cytochrome P450 interaction profile. In clinical trials, the resulting compound from our extensive research program, asundexian (BAY 2433334), proved to possess the desired DMPK properties for once-daily oral dosing, and even more importantly, the initial pharmacological hypothesis was confirmed.
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000600501 7001_ $$aAckerstaff, Jens$$b1
000600501 7001_ $$aJiménez Núñez, Eloísa$$b2
000600501 7001_ $$aTeller, Henrik$$b3
000600501 7001_ $$aEllerbrock, Pascal$$b4
000600501 7001_ $$aMeier, Katharina$$b5
000600501 7001_ $$aHeitmeier, Stefan$$b6
000600501 7001_ $$aTersteegen, Adrian$$b7
000600501 7001_ $$aStampfuss, Jan$$b8
000600501 7001_ $$00000-0002-2968-638X$$aLang, Dieter$$b9
000600501 7001_ $$aSchlemmer, Karl-Heinz$$b10
000600501 7001_ $$aSchaefer, Martina$$b11
000600501 7001_ $$aGericke, Kersten M.$$b12
000600501 7001_ $$aKinzel, Tom$$b13
000600501 7001_ $$00000-0003-4978-9842$$aMeibom, Daniel$$b14
000600501 7001_ $$aSchmidt, Martina$$b15
000600501 7001_ $$aGerdes, Christoph$$b16
000600501 7001_ $$00000-0003-1246-3603$$aFollmann, Markus$$b17
000600501 7001_ $$00000-0002-4228-2347$$aHillisch, Alexander$$b18
000600501 773__ $$0PERI:(DE-600)1491411-6$$a10.1021/acs.jmedchem.3c00795$$gVol. 66, no. 17, p. 12203 - 12224$$n17$$p12203 - 12224$$tJournal of medicinal chemistry$$v66$$x0095-9065$$y2023
000600501 8564_ $$uhttps://pubs.acs.org/doi/full/10.1021/acs.jmedchem.3c00795
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