Wrobel Jay, Steffan Robert, Bowen S Marc, Magolda Ronald, Matelan Edward, Unwalla Rayomand, Basso Michael, Clerin Valerie, Gardell Stephen J, Nambi Ponnal, Quinet Elaine, Reminick Jason I, Vlasuk George P, Wang Shuguang, Feingold Irene, Huselton Christine, Bonn Tomas, Farnegardh Mathias, Hansson Tomas, Nilsson Annika Goos, Wilhelmsson Anna, Zamaratski Edouard, Evans Mark J
Chemical and Screening Sciences, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA.
J Med Chem. 2008 Nov 27;51(22):7161-8. doi: 10.1021/jm800799q.
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.
制备了一系列取代的2-苄基-3-芳基-7-三氟甲基吲唑作为肝X受体（LXR）调节剂。与1（T0901317）相比，这些化合物在反式激活试验中为部分激动剂，并且在LXRα上的效力和功效相对于LXRβ略弱。该系列中的先导化合物12（WAY-252623）和13（WAY-214950）在HepG2细胞中的脂质积累比强效的完全激动剂1和3（WAY-254011）少，但在THP-1泡沫细胞中胆固醇流出方面的功效与1和3相当，尽管效力较弱。化合物13在低密度脂蛋白受体（LDLR）基因敲除小鼠中使主动脉病变面积减少的程度与3或阳性对照2（GW3965）相当。在一个为期7天的仓鼠模型中，当以能使十二指肠和肝脏中ABCA1和ABCG1基因表达同等程度升高的剂量比较化合物时，化合物13使血浆甘油三酯（TG）升高的倾向比3小。与先前报道的2的结果相反，13缺乏TG效应与其无法增加肝脏脂肪酸合酶（FAS）基因表达相关，而3可使该基因表达上调4倍。这些结果表明，吲唑类化合物如13作为治疗剂可能具有改善的特性。
