Regioselectivity of thiouracil alkylation: Application to optimization of Darapladib synthesis

Abstract Darapladib is one of the most potent Lp-PLA 2 (Lipoprotein-associated phospholipase A 2 ) inhibitor with an IC 50 of 0.25 nM. We demonstrate that a crucial step of Darapladib synthesis was not correctly described in the literature, leading to the production of wrong regioisomers. Moreover we show that the inhibitory activity is directly linked to the position on N1 since compounds bearing alkylation on different sites have potentially less interaction within the active site of Lp-PLA 2 .