Journal Article

PUBDB-2023-08014

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Design and Preclinical Characterization Program toward Asundexian (BAY 2433334), an Oral Factor XIa Inhibitor for the Prevention and Treatment of Thromboembolic Disorders

Roehrig, S. (Corresponding author) ; Ackerstaff, J. ; Jiménez Núñez, E. ; Teller, H. ; Ellerbrock, P. ; Meier, K. ; Heitmeier, S. ; Tersteegen, A. ; Stampfuss, J. ; Lang, D. ; Schlemmer, K.-H. ; Schaefer, M. ; Gericke, K. M. ; Kinzel, T. ; Meibom, D. ; Schmidt, M. ; Gerdes, C. ; Follmann, M. ; Hillisch, A.

2023
ACS Washington, DC

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Please use a persistent id in citations: doi:10.1021/acs.jmedchem.3c00795  doi:10.3204/PUBDB-2023-08014

Abstract: 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.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P14 (PETRA III)

Appears in the scientific report 2023

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; Index Chemicus ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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