Discovery of a High Affinity, Orally Bioavailable Macrocyclic FXIa Inhibitor with Antithrombotic Activity in Preclinical Species

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.