Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA₂)

Abstract

Lp-PLA has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.

Lipoprotein‐associated phospholipase A2: The story continues

“…In this context, several compounds with diverse scaffolds have been identified as potent Lp‐PLA2 inhibitors, providing several excellent probe molecules. In addition, benefiting from the FBLD strategy, recently reported Lp‐PLA2 inhibitors exhibit favorable physicochemical properties and PK profiles . In terms of their clinical applications, although Lp‐PLA2 inhibitors failed to reduce the incidence of CVD events, they indeed showed significant therapeutic effects on microvascular diseases such as DR and AD.…”

“…Compared with darapladib, compound 3 efficiently utilizes the groove above Trp298 to enhance the potency, as Trp298 appears to be essential for substrate interactions with Ser273. Since the groove extends toward the solvent, occupying the space can also modulate the physicochemical properties of the ligand …”

“…The compound showed comparable inhibitory potency to darapladib in whole human plasma assays ( 3 , IC 50 = 32 nM and darapladib, IC 50 = 35 nM) and the drop off between the Lp‐PLA2 assay and plasma assay was small. Furthermore, PK and safety evaluations demonstrated that compound 3 provided an attractive PK profile and excellent physicochemical properties, suggesting a promising starting point for further lead optimization …”

“…Indeed, this favors the discovery of novel Lp‐PLA2 inhibitors with favorable physicochemical properties. Inspired by the successful application of FBLD, we can facilitate the development of Lp‐PLA2 inhibitors by introducing other emerging technologies …”

“…In addition, we highlighted recent advances in Lp‐PLA2 and Lp‐PLA2 inhibitors. The newly established crystal structures of Lp‐PLA2 after soaking with different inhibitors and the identification of new binding pockets may advance the discovery of potent and selective inhibitors . Notably, the successful application of fragment‐based lead discovery (FBLD) in developing Lp‐PLA2 inhibitors provides a referential practice for other targets’ lead discovery.…”