AZ876 is a potent, highly selective LXR agonist with Ki/EC50 of 7/6 nM and 11/73 nM for hLXRα and hLXRβ respectively.

LXR:6 nM (EC50, cell free)

AZ876抑制了与肥大和纤维化相关基因的上调，并进一步抑制了促肥大和促纤维化的TGFβ-Smad2/3信号通路。在心肌细胞中，AZ876处理后的细胞中，苯肾上腺素刺激的细胞肥大显著减少。在心脏成纤维细胞中，AZ876阻止了TGFβ和血管紧张素II诱导的成纤维细胞胶原合成，并抑制了肌成纤维细胞标志物α-平滑肌肌动蛋白[2]的上调。

低剂量AZ876在血浆或肝脂肪上无影响，相比之下，高剂量AZ876升高了血浆中的甘油三酯并降低了胆固醇水平。低剂量AZ876减少了病变面积；而高剂量AZ876显著减少了病变面积、病变数量及严重性。AZ876的任何剂量都不影响病变组成[1]。在C57Bl6/J小鼠中，通过横向主动脉缩窄（TAC）引发心脏肥大，持续6周。在此期间，小鼠饲料中添加或不添加AZ876（20μmol/kg/天）。在小鼠心脏中，LXRα蛋白表达量因TAC反应上调约7倍。LXR激活剂AZ876缓和了这一增加，并显著减少了由TAC引起的心脏重量增加、心肌纤维化和心脏功能障碍，同时不影响血压[2]。

Binding vectors for His-tagged protein production were prepared by inserting the ligand-binding domain cDNA of human LXRα (amino acids 205–447) in pET28 and the ligand-binding domain cDNA of LXRβ (amino acids 216–461) in pET24D. Proteins were expressed in Escherichia coli and purified on Ni+ columns. Binding assays using LXRα and LXRβ protein were run by adding reagents to Wallac Isoplate 1450–514. Briefly, each 96 plate well contained assay buffer (20 mM Tris pH 7.5, 80 mM NaCl, 2 mM dithiothreitol, 0.125% Chaps and 10% glycerol), 0.1 mg SPA beads (polylysine-coated yttrium silicate beads), LXRα (0.5 μg) or LXRβ (0.25 μg), 30 nM 3H-ligand (specific activity of 473 Kbq/nmol) and test compound in a 10-point dose-response dilution. The assay mixture was shaken gently for 2 h on a plate shaker after which the beads were allowed to settle for 1 hour before counting. Transactivation vectors were prepared by inserting the ligand-binding domain cDNA sequences of human or mouse LXRα and LXRβ in frame with the yeast Gal4 transcription factor DNA binding domain and the nuclear localization signal from the T-antigen of polyomavirus in the eucaryotic expression vector pSG5. The ligand-binding domain cDNA of human LXRα and LXRβ was the same as mentioned previously. The mouse sequence corresponded to amino acids 203–445 for LXRα and amino acids 201–446 for LXRβ. The vectors were co-transfected with a pGL3 luciferase reporter plasmid containing a minimal SV40 promoter and five copies of the UAS Gal4 recognition site into U2/OS osteosarcoma cells. Ligands were added as 10-point dose-response curves and then luciferase activity was measured after 48 h [1].

Cardiac hypertrophy was induced in male C57Bl6/J mice via transverse aortic constriction (TAC) for 6 weeks. During this period, sham and TAC-operated mice were randomized to receive either regular chow (control) or chow supplemented with AZ876 (20 μmol/kg/day). Cardiac function was assessed with echocardiography and invasive haemodynamics. In vitro studies were performed in isolated neonatal rat ventricular myocytes (NRVMs) and adult rat cardiac fibroblasts. Leucine and proline tracer assays were used to measure protein and collagen synthesis, respectively [2].