Atherosclerosis is a disorder of the arteries characterized by the formation of hard structures called atherosclerotic plaques. It is a prevalent disorder, accounting for one third of all deaths in North America.
Atherosclerotic Plaque Formation
Formation of atherosclerotic plaques is a progressive process and the exact cause is unknown but it is believed to originate from damage to the arterial wall. One possible cause of this damage is oxidized low-density lipoprotein (LDL). Initially a 'fatty streak' forms in the artery wall, which damages the blood vessel and initiates an inflammatory process. Monocytes invade the artery wall and differentiate into macrophages. Macrophages absorb the oxidized low density lipoproteins (LDL), form 'foam cells' and develop into a 'fatty streak'. Foam cells are unable to process oxidized-LDL and they ultimately grow and rupture, depositing more oxidized-LDL into the artery wall, causing the invasion of more macrophages and propagating the inflammatory response. Eventually muscle cells enlarge and form a fibrous cap over the fatty plaque, resulting in narrowing of the artery. The fibrous cap is prone to rupture and subsequent exposure of the plaque core leads to acute thrombus formation and myocardial infarction.
Risk Factors and Pharmacological Intervention
Risk factors for the development of atherosclerosis include hyperlipidemia, hypertension, diabetes, male gender and advanced age. Current treatment options comprise the cholesterol lowering drugs statins and surgical intervention. New pharmacological targets include PPAR, cytokines, matrix metalloproteases and adhesion molecules.
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A clinically viable, highly brain-penetrant LXRα-partial/LXRβ-full agonist with binding Ki of 33 nM/248 nM; selectively kills GBM cells in an LXRβ- and cholesterol-dependent fashion, causing tumor regression and prolonged survival in mouse models.
SB-435495 is a potent, orally active inhibitor of Lp-PLA2 with IC50 of 0.06 nM; inhibits the enzyme in whole human plasma with IC50 of 3 nM; shows little interaction with other CYP450 enzymes (CYP450 IC50: 1A2>100 mM, 2C9>100 uM, 2C19>40 uM, 2D6=37 uM); effectively suppresses BRB breakdown in streptozotocin-diabetic Brown Norway rats,.
A potent Lp-PLA2 inhibitor with IC50 of 0.25 nM; shows an enhanced in vitro and in vivo profile versus SB-435495.
Anacetrapib (MK 0859) is a potent, orally active cholesteryl ester transfer protein (CETP) inhibitor with IC50 of 7.9 nM and 11.8 nM for rhCETP and C13S CETP mutant, respectively; inhibits CETP-mediated cholesterol exchange, resulting in elevated HDL-cholesterol levels and reductions in LDL-cholesterol levels, demonstrates potential to treat elevated cholesterol levels in an effort prevent cardiovascular disease.
PD-146176 is a potent, selective, non-competitve inhibitor of 15-lipoxygenase (15-LOX) with Ki of 197 nM; shows no demonstrable effect on 5-LOX, 12-LOX, COX-1 or COX-2; significantly abrogates SAT1-induced ferroptosis, inhibits amyloid β protein aggregate formation without changing total levels of amyloid β precursor protein (APP) in cells stably expressing APP.
MK-0354(MK0354) is a potent, selective niacin receptor GPR109A partial agonist with EC50 of 1.65 and 1.08 uM for hGPR109A and mGPR109A in the whole cell cAMP assays; shows no interaction with any other target in a panel of over 120 other proteins; MK-0354 is a competitive inhibitor of 3H-nicotinic acid binding to hGPR109a with Ki of 505 nM, fully inhibits isoproterenol stimulated lipolysis in human adipocytes with IC50 of 3.1 uM, also is a competitive antagonist of nicotinic acid-induced MAPK signaling in cells overexpressing either mGPR109a or hGPR109a; possesses plasma FFA lowering effects in mice comparable to those of nicotinic acid, does not induce vasodilation.
BMS-779788 (XL-652;BMS-788;EXEL-04286652) is a potent, highly selective partial LXR agonist with Ki of 14 nM for LXRβ, shows moderate selectivity (5-fold) over LXRα (Ki=68 nM); only has activity for PXR (ECU0=2 uM) in a panel of 14 NHRs; induces LXR target genes in blood in vivo (EC50=610 nM); increases in biliary cholesterol and decreases in phospholipid and bile acid in animal models.
Terutroban (S-18886) is a potent, selective antagonist of the thromboxane receptor (Prostanoid TP receptor) that blocks thromboxane induced platelet aggregation and vasoconstriction;
Torcetrapib (CP-529414) is a potent cholesteryl ester transfer protein (CETP) inhibitor with IC50 of 37 nM; shows the potential to treat hypercholesterolemia (elevated cholesterol levels) and prevent cardiovascular disease.
CI-976 (PD 128042) is a potent, selective, orally bioavailable inhibitor of ACAT-1 (Acetyl-CoA acetyltransferase 1) with IC50 of 73 nM; decreases plasma total cholesterol, very low density lipoprotein (VLDL) cholesterol, LDL cholesterol, apolipoprotein B, liver cholesteryl esters, and VLDL and LDL cholesteryl ester content in rabbits.
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