Lp-PLA2 (Lipoprotein-associated phospholipase A2) is a calcium-independent serine lipase of 50-kDa that hydrolyzes the acetyl group at the sn-2 position of the platelet-activating factor. Importantly, Lp-PLA2 circulates in plasma bound mainly to low-density lipoprotein (LDL), and promotes vascular inflammation. Specifically, HDL-associated Lp-PLA2 may substantially contribute to HDL antiatherogenic activities. Mainly, Lp-PLA2 is an enzyme produced by inflammatory cells and hydrolyzes oxidized phospholipids in LDL. Besides, Lp-PLA2 can elicit a broad range of proinflammatory and proapoptotic effects in blood vessels and has been proposed as a predictive biomarker in stroke, atherosclerosis, and coronary heart disease.

In this article, we will introduce a potent Lp-PLA2 inhibitor, SB-435495.

SB-435495 is a potent, selective, reversible, non-covalent, and orally active Lp-PLA2 inhibitor with an IC50 of 0.06 nM. Besides, SB-435495 inhibits CYP450 3A4 with an IC50 of 10 μM and the black membrane permeability is 0.017 cm/h. Moreover, SB-435495 (5 μM; 24 h) significantly inhibits the expression of Lp-PLA2 protein, while increasing the expression levels of AMPKα and phosphorylated-AMPKα (T172) in oxLDL-exposed HUVECs. Meanwhile, SB-435495 (5 μM; 24-72 h) significantly increases cell viability and NO expression and significantly decreases ET-1 expression in the oxLDL-exposed HUVECs.

SB-435495 (0-100 μM) inhibits Lp-PLA2 in BN rat plasma with an IC50 of 8.8 nM. Moreover, SB-435495 (10 mg/kg; p.o.; once) inhibits plasma Lp-PLA2 in the WHHL rabbit. Meanwhile, SB-435495 (0.25, 1, 5, 10 mg/kg; i.p.; daily for 28 days ) reduces plasma Lp-PLA2 activity levels to 72.8%, 57.5%, 33.5%, and 19.1%, respectively in diabetic rats. In addition, SB-435495 (10 mg/kg; i.p.; daily for 28 days) effectively suppresses blood-retinal barrier (BRB) breakdown in Streptozotocin-diabetic brown norway rats.

All in all, SB-435495 is a potent Lp-PLA2 inhibitor and has the potential for the research of diabetes.


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