Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A₂ Inhibitors

Abstract

Inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) has been suggested to be a promising therapeutic strategy for several inflammation-associated diseases, including atherosclerosis, Alzheimer's disease, and diabetic macular edema. Herein, we report the discovery of a novel series of Lp-PLA2 inhibitors constructed on an imidazo[1,2-a]pyrimidine scaffold through a conformational restriction strategy. Structure-activity relationship (SAR) analysis resulted in the identification of several compounds with high potency in vitro and good metabolic stability in liver S9 fractions. Compounds 7c and 14b selected for further exploration in vivo demonstrated excellent pharmacokinetic profiles and exhibited significant inhibitory efficacy in SD rats upon oral dosing.

Lipoprotein‐associated phospholipase A2: The story continues

“…The overall inhibition was also comparable to 50 mg/kg darapladib and higher than that for 25 mg/kg GSK2647544. Taken together, these results suggest that the imidazo[1,2‐a]pyrimidine derivatives harbor reasonable physicochemical properties, and are potent, orally bioavailable Lp‐PLA2 inhibitors …”

“…This substitution resulted in improved solubility and an enhanced overall PK profile. 68 However, although darapladib can be used orally, it displayed poor plasma exposure (data from GSK 238 and our group 244 ), probably owing to its high molecular weight and strong lipophilicity (MW = 667, clogP = 8.3). Since 2012, F I G U R E 9 The discovery of darapladib and rilapladib.…”

“…However, although darapladib can be used orally, it displayed poor plasma exposure (data from GSK and our group), probably owing to its high molecular weight and strong lipophilicity (MW = 667, clog P = 8.3). Since 2012, GSK has successively patented a series of novel pyrimidone derivatives as Lp‐PLA2 inhibitors .…”

“…Taken together, these results suggest that the imidazo [1,2-a] pyrimidine derivatives harbor reasonable physicochemical properties, and are potent, orally bioavailable Lp-PLA2 inhibitors. 244 To obtain novel Lp-PLA2 inhibitors with simplified structures, we also made changes to the pyrimidone scaffold, focusing on the right-hand side of the structure. Unlike the compounds reported by GSK, we unfolded the fused heterocycle to determine the resulting effects on PK and PD properties.…”

pCRP-mCRP Dissociation Mechanisms as Potential Targets for the Development of Small-Molecule Anti-Inflammatory Chemotherapeutics

“…The most successful drugs against LpPLA 2 are pyrimidin-4-ones of the darapladib class 1 (Figure 2 ) ( 36 ) discovered by modification of lead compounds unearthed by high throughput screening programs at GSK ( 37 – 39 ). A range of analogs, based on the darapladib motif have been studied but do not display improved activity ( 40 , 41 ), although some imidazopyrimidine derivatives, such as 2 , do exhibit improved bioavailability ( 42 ). Unfortunately, darapladib failed Phase III clinical trials due to a failure to alleviate the risk of cardiovascular death or stroke in coronary heart disease patients ( 43 , 44 ).…”