Macrocyclic inhibitors of Factor XIa: Discovery of alkyl-substituted macrocyclic amide linkers with improved potency

Abstract Optimization of macrocyclic inhibitors of FXIa is described which focused on modifications to both the macrocyclic linkerand the P1 group. Increases in potencywere discovered through interactions with a key hydrophobic region near the S1 prime pocket by substitution of the macrocyclic linkerwith small alkyl groups. Both the position of substitution and the absolute stereochemistry of the alkyl groups on the macrocyclic linkerwhich led to improved potencyvaried depending on the ring sizeof the macrocycle. Replacement of the chlorophenyltetrazole cinnamide P1 in these optimized macrocycles reduced the polar surface areaand improved the oral bioavailability for the series, albeit at the cost of a decrease in potency.