TY  - JOUR
AU  - Roehrig, Susanne
AU  - Ackerstaff, Jens
AU  - Jiménez Núñez, Eloísa
AU  - Teller, Henrik
AU  - Ellerbrock, Pascal
AU  - Meier, Katharina
AU  - Heitmeier, Stefan
AU  - Tersteegen, Adrian
AU  - Stampfuss, Jan
AU  - Lang, Dieter
AU  - Schlemmer, Karl-Heinz
AU  - Schaefer, Martina
AU  - Gericke, Kersten M.
AU  - Kinzel, Tom
AU  - Meibom, Daniel
AU  - Schmidt, Martina
AU  - Gerdes, Christoph
AU  - Follmann, Markus
AU  - Hillisch, Alexander
TI  - Design and Preclinical Characterization Program toward Asundexian (BAY 2433334), an Oral Factor XIa Inhibitor for the Prevention and Treatment of Thromboembolic Disorders
JO  - Journal of medicinal chemistry
VL  - 66
IS  - 17
SN  - 0095-9065
CY  - Washington, DC
PB  - ACS
M1  - PUBDB-2023-08014
SP  - 12203 - 12224
PY  - 2023
AB  - Activated 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.
LB  - PUB:(DE-HGF)16
C6  - 37669040
UR  - <Go to ISI:>//WOS:001062618600001
DO  - DOI:10.1021/acs.jmedchem.3c00795
UR  - https://bib-pubdb1.desy.de/record/600501
ER  -