Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2

Lipoprotein-associated
phospholipase A2 (Lp-PLA2) is a promising
therapeutic target for atherosclerosis, Alzheimer’s disease,
and diabetic macular edema. Here we report the identification of novel
sulfonamide scaffold Lp-PLA2 inhibitors derived from a relatively
weak fragment. Similarity searching on this fragment followed by molecular
docking leads to the discovery of a micromolar inhibitor with a 300-fold
potency improvement. Subsequently, by the application of a structure-guided
design strategy, a successful hit-to-lead optimization was achieved
and a number of Lp-PLA2 inhibitors with single-digit nanomolar potency
were obtained. After preliminary evaluation of the properties of drug-likeness
in vitro and in vivo, compound 37 stands out from this
congeneric series of inhibitors for good inhibitory activity and favorable
oral bioavailability in male Sprague–Dawley rats, providing
a quality candidate for further development. The present study thus
clearly demonstrates the power and advantage of integrally employing
fragment screening, crystal structures determination, virtual screening,
and medicinal chemistry in an efficient lead discovery project, providing
a good example for structure-based drug design.