Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties

Compound 2 was previously identified as a potent inhibitor of factor XIa lacking oral bioavailability. A structure-based approach was used to design analogs of 2 with novel P1 moieties with good selectivity profiles and oral bioavailability. Further optimization of the P1 group led to the identification of a 4-chlorophenyltetrazole P1 analog, which when combined with further modifications to the linker and P2' group provided compound 32 with FXIa K-i = 6.7 nM and modest oral exposure in dogs. (C) 2015 Elsevier Ltd. All rights reserved.