1. Discovery of a High Affinity, Orally Bioavailable Macrocyclic FXIa Inhibitor with Antithrombotic Activity in Preclinical Species
- Author
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Arunachalam Arumugam, Dietmar A. Seiffert, Arvind Mathur, Joanna J. Zheng, Ruth R. Wexler, Jeon Yoon T, Premsai Rai Neithnadka, Earl J. Crain, Paul J. Gilligan, Patrick Y.S. Lam, Yiming Wu, Mahammed Kaspady, Pancras C. Wong, Tianan Fang, Silvi A. Chacko, William R. Ewing, Pabbisetty Kumar Balashanmuga, Zhen Lou, Steven Sheriff, Joseph M. Luettgen, Joseph E. Myers, Wu Yang, Karen A. Rossi, Richard Rampulla, James R. Corte, Amy Lai, Charles G. Clark, Jeffrey M. Bozarth, Yufeng Wang, and Sivashankaran Raju
- Subjects
Models, Molecular ,Proteases ,Macrocyclic Compounds ,Drug Evaluation, Preclinical ,Administration, Oral ,Biological Availability ,Pharmacology ,Crystallography, X-Ray ,01 natural sciences ,Factor XIa ,Serine ,Structure-Activity Relationship ,03 medical and health sciences ,Dogs ,Fibrinolytic Agents ,Pharmacokinetics ,In vivo ,Drug Discovery ,Antithrombotic ,Animals ,Humans ,Structure–activity relationship ,030304 developmental biology ,0303 health sciences ,Chemistry ,0104 chemical sciences ,Bioavailability ,010404 medicinal & biomolecular chemistry ,Molecular Medicine ,Rabbits ,Hydrophobic and Hydrophilic Interactions ,Linker - Abstract
Oral factor XIa (FXIa) inhibitors may provide a promising new antithrombotic therapy with an improved benefit to bleeding risk profile over existing antithrombotic agents. Herein, we report application of a previously disclosed cyclic carbamate P1 linker which provided improved oral bioavailability in the imidazole-based 13-membered macrocycle to the 12-membered macrocycle. This resulted in identification of compound 4 with desired FXIa inhibitory potency and good oral bioavailability but high in vivo clearance. Further structure-activity relationship (SAR) studies of heterocyclic core modifications to replace the imidazole core as well as various linkers to the P1 group led to the discovery of compound 6f, a potent FXIa inhibitor with selectivity against most of the relevant serine proteases. Compound 6f also demonstrated excellent pharmacokinetics (PK) profile (high oral bioavailability and low clearance) in multiple preclinical species. Compound 6f achieved robust antithrombotic efficacy in a rabbit efficacy model at doses which preserved hemostasis.
- Published
- 2020