The novel oral anticoagulants have largely addressed many limitations of vitamin K antagonists, the previous standard of care. However, there still remains a medical need for novel antithrombotic agents with an improved therapeutic index. Human genetic and epidemiologic data suggest that FXIa inhibition may provide a new antithrombotic therapy with an improved therapeutic benefit relative to bleeding risk profile. We and others have reported preclinical models with FXIa inhibitors which show an improved therapeutic index as compared to other mechanisms. Clinical support for this concept was demonstrated with an antisense oligonucleotide which reduced FXI expression and provided efficacy superior to enoxaparin without increasing bleeding risk in a knee arthroplasty Phase II study. We have previously reported the discovery of potent 12- and 13-membered macrocyclic FXIa inhibitors and the subsequent optimization of the substitutions on the macrocycle linkers through structure-based drug design. Our initial disclosure showed that exquisite potency could be achieved using a chlorophenyltetrazole P1 group to interact with the S1 of FXIa.  However, these analogs generally had poor PK properties due to their high PSA (polar surface areas). In this presentation, we will describe our effort to improve oral bioavailability by removing an H-bond donor from the P1 group via cyclization to form conformation-constrained analogs and by reducing overall PSA via removal of the tetrazole group. Further SAR studies of P1 groups as well as heterocyclic core modifications led to the discovery of sub-nanomolar inhibitors with good oral bioavailability and selectivity against most relevant serine proteases. A key compound will be presented that showed superior PK properties (excellent oral bioavailability and low clearance) in multiple preclinical species (cyno, dog, and rat). In the rabbit models, this compound achieved robust antithrombotic efficacy at doses which did not prolong cuticle bleeding time.<br/>

Discovery of potent and orally bioavailable macrocyclic FXIa inhibitors

254th National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.