Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties. Issue 7 (1st April 2015) - Pinto, Donald J.P.
Graphical abstract: Abstract: Compound2 was previously identified as a potent inhibitor of factor XIa lacking oral bioavailability. A structure-based approach was used to design analogs of2 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 compound32 with FXIa K i = 6.7 nM and modest oral exposure in dogs.