Indazole-Based Liver X Receptor (LXR) Modulators with Maintained Atherosclerotic Lesion Reduction Activity but Diminished Stimulation of Hepatic Triglyceride Synthesis

Abstract

A series of substituted 2-benzyl-3-aryl-7-trifluoromethylindazoles were prepared as LXR modulators. These compounds were partial agonists in transactivation assays when compared to 1 (T0901317) and were slightly weaker with respect to potency and efficacy on LXRalpha than on LXRbeta. Lead compounds in this series 12 (WAY-252623) and 13 (WAY-214950) showed less lipid accumulation in HepG2 cells than potent full agonists 1 and 3 (WAY-254011) but were comparable in efficacy to 1 and 3 with respect to cholesterol efflux in THP-1 foam cells, albeit weaker in potency. Compound 13 reduced aortic lesion area in LDLR knockout mice equivalently to 3 or positive control 2 (GW3965). In a 7-day hamster model, compound 13 showed a lesser propensity for plasma TG elevation than 3, when the compounds were compared at doses in which they elevated ABCA1 and ABCG1 gene expression in duodenum and liver at equal levels. In contrast to results previously published for 2, the lack of TG effect of 13 correlated with its inability to increase liver fatty acid synthase (FAS) gene expression, which was up-regulated 4-fold by 3. These results suggest indazoles such as 13 may have an improved profile for potential use as a therapeutic agent.

LXR ligand lowers LDL cholesterol in primates, is lipid neutral in hamster, and reduces atherosclerosis in mouse

“…In vitro characterization of WAY-252623 as a partial agonist has been described recently ( 19 ). Briefl y, WAY-252623 preferentially binds LXR ␤ (IC 50 = 24 nM) versus LXR ␣ (IC 50 = 179 nM) and demonstrates full agonism for upregulating macrophage ABCA1 gene expression and cholesterol effl ux.…”

“…like properties and effi cacy in murine models of atherosclerotic lesion progression was reported recently ( 19 ). In this report, the lead compound from this series, WAY-252623 (LXR-623), a novel partial LXR agonist, is profi led more extensively in several animal models, including a nonhuman primate.…”

“…Compound, WAY-252623 2-(2-chloro-4-fl uorobenzyl)-3-(4-fl uorophenyl)-7-(trifl uoromethyl)-2H-indazole was synthesized at Wyeth Research in Collegeville, PA ( 19 ). LXR reference ligands TO901317, GW3965, and WAY-254011 were prepared as described ( 17,22 ) and the farnesoid X receptor (FXR) ligand 3-(2,6-dichlorophenyl)-4-(3"-carboxy-2-chloro-stilben-4-yl) oxymethyl-5-isopropyl-isoxazole [( 23 ), GW4064] was synthesized at Wyeth.…”

“…The area under the curve of each peak representing VLDL, LDL, and HDL was integrated using Waters Millennium software 4.0 (Waters Corp., Milford, MA) and each lipoprotein fraction was quantifi ed by multiplying the total cholesterol value by the relative percent area of each respective chromatographic peak. Hepatic lipids, cholesterol, and triglyceride concentrations in liver were determined by Analytics (Gaithersburg, MD) for primate studies or internally at Wyeth using methods previously described ( 19 ).…”

“…Male Golden Syrian hamsters, 5-6 weeks of age (90-100 g, Harlan, Indianapolis, IN), were randomized by body weight and housed two per cage in plastic cages with ad libitum access to water and diet (Purina Rodent Chow 5001) as described previously ( 19 ). Briefl y, animals were allowed to acclimate for 1 week under standard conditions with a 12:12 h light/dark cycle (lights on at 0600 h) with temperature controlled at 22 ± 2 o C. Animals were divided into treatment groups and compounds were administered by gavage.…”