Discovery of Potent and Orally Active Lipoprotein-Associated Phospholipase A₂ (Lp-PLA₂) Inhibitors as a Potential Therapy for Diabetic Macular Edema

Abstract

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is considered to be a promising therapeutic target for several inflammation-associated diseases. Herein, we describe the discovery of a series of pyrimidone derivatives as Lp-PLA2 inhibitors. Systematic structural modifications led to the identification of several pyrimidone compounds with promising in vitro inhibitory potency and pharmacokinetic properties. Compound 14c, selected for in vivo evaluation, demonstrated decent pharmacokinetic profiles and robust inhibitory potency against Lp-PLA2 in Sprague-Dawley (SD) rats. Furthermore, 14c significantly inhibited retinal thickening in STZ-induced diabetic SD rats as a model of diabetic macular edema (DME) after oral dosing for 4 weeks. Taken together, these results suggested that 14c can serve as a valuable lead in the search for new Lp-PLA2 inhibitors for prevention and/or treatment of DME.

Lipoprotein‐associated phospholipase A2: The story continues

“…Importantly, these findings also support that Lp‐PLA2 inhibitors, such as darapladib, might be valuable in eye diseases characterized by vascular abnormalities . Additionally, our group reported a novel Lp‐PLA2 inhibitor that could inhibit retinal thickening in STZ‐induced diabetic SD rats after oral dosing for 4 weeks, and further comprehensive studies are currently underway …”

“…36 Additionally, our group reported a novel Lp-PLA2 inhibitor that could inhibit retinal thickening in STZ-induced diabetic SD rats after oral dosing for 4 weeks, and further comprehensive studies are currently underway. 194 To scrutinize the ability of an Lp-PLA2 inhibitor to reduce edema and improve vision in subjects with centerinvolved DME, a randomized, double-masked phase IIa clinical trial was performed, in which darapladib 160 mg or placebo monotherapy was orally administered once daily for 3 months, and patients were followed up monthly for 4 months. Consequently, approximately 4 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in bestcorrected visual acuity (BCVA) and 60 mm central subfield thickness improvements were observed in the darapladib treatment group, whereas these parameters were not significantly enhanced in the placebo group.…”

Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2

“…Moreover, 36 (Fig. 5) significantly inhibited retinal thickening in streptozotocin-induced diabetic SD rats, as a model of DME, after oral dosing for 4 weeks [119].…”

“…Recently, the crystal structures of human LpPLA 2 bound with darapladib and inhibitor 32 (Fig. 5, IC 50 1.7 nM against recombinant human LpPLA 2 ) [119] were determined. Briefly, structural investigation into the LpPLA 2 /darapladib and LpPLA 2 /32 complexes identified a fairly open, large, relatively hydrophobic and rigid binding pocket.…”

Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) as a therapeutic target to prevent retinal vasopermeability during diabetes

“…Darapladib is a selective inhibitor of Lp-PLA 2 with demonstrable efficacy against atherogenesis in preclinical models (15). In diabetic and hypercholesterolemic pigs, darapladib prevents leakage of circulating IgG into the brain parenchyma, suggesting a protective effect of BBB function (17) while some pyrimidone derivatives have been shown to inhibit Lp-PLA 2 activity and reduce morphological changes to retinal layers in diabetic rats (26). However, the consequence or mechanism of Lp-PLA 2 inhibition on retinal vascular permeability has not yet been investigated.…”