Eliquis (apixaban), a direct inhibitor of factor Xa (FXa), was approved by the European Commission on May 18, 2011 for prevention of venous thromboembolic events (VTE) in adult patients who
have undergone elective hip or knee replacement surgery. The discovery of apixaban was the culmination of a succession of novel and innovative medicinal chemistry discoveries starting with the
identification of nonpeptide leads, rational drug design using computer-aided and X-ray crystallographic information, and the building of drug-like properties through the systematic replacement of
basic groups with neutral moieties. Apixaban arose from modifications to razaxaban by constraining a pyrazole amide to form a bicyclic pyrazolo-pyridinone scaffold. Optimization of the P1 group
resulted in the identification of the nonbasic methoxy phenyl group, while a P4 piperidinone improved the balance of potency and pharmacokinetics with low Vdss. The synthesis of apixaban begins with
the generation of a hydrazone of 4-methoxyaniline which is then used in a 3+2 cycloaddition with a dihydropiperidinone to form a bicyclic pyrazolo-pyridinone scaffold. The distal piperidinone group
is installed using an Ullmann coupling reaction followed by aminolysis of an ethyl ester on the pyrazole ring to complete the synthesis of apixaban.