影响要求保护的发明的基本 和新颖的（多个）特征。体现本发明的所有的组合物和使用它们的方法可以，在替代的实 施方案中，由过渡术语"包括"，"基本上由......组成"和"由......组成"中的任一个具 体地限定。
[0139] 实施例5
[0140] 在动物模型中测试功效
[0141] 在雄性小鼠（C57BL/6小鼠）中测试SBC-115076和SBC-110034的功效。在气候 控制条件下以每笼四只动物饲养小鼠，温度（20_24°C )，湿度（60-70% )，以及交替12小时 光/暗循环。将小鼠分为五组，如图7所示。一组喂商用食物饮食（Prolab RMH 3000, PMI feeds, St. Louis, M0)以用作阴性对照，而其他四组饲喂高脂饮食（TD. 06414)，其从脂肪提 供热量的60%。自由提供水。每周采集血浆一次以监测LDL水平。4个星期饲喂高脂饮 食后，小鼠被随机分配到几组中的一组，使得不同组间的平均LDL水平相等。用媒介物处 理喂食高脂饮食的四组小鼠中的一组并用作阳性对照，而其他三组中的每一组每天用8mg/ kg的其中一种上述化合物皮下地处理两周。在药物施用之后每周两次经由每管含有2USP 单位的铵肝素的肝素化毛细管（Carolina，Burlington，NC)从眼眶后静脉丛采集血液样品 (75yl)。通过在室温下离心（5000x g)5分钟立即分离血浆并保持在-80°C下直至测定脂 质分布。酶促测定血浆胆固醇，LDL-C、HDL-C和甘油三酯水平。此外，为PCSK9抑制剂的潜 在多效性效果使用ELISA和多重测定法测定PCSK9和趋化因子/细胞因子的血浆水平。
[0142] 获得的数据表明，SBC-115076和SBC-110034在饲喂高脂肪食物的小鼠中降低胆 固醇的水平。图8显示用SBC-115076获得数据，其表明相对于高脂饮食动物水平，两周之 后SBC-110736示出总胆固醇水平的平均32%的减少（P〈0. 01)，以及趋向恢复到正常饮食 胆固醇水平的平均50%减少（P〈0. 01)。
[0143] 用阿托伐他汀（40mg/kg，三周）进行第二项研究。数据显示，利用阿托伐他汀，相 对于高脂饮食动物水平，三周之后总胆固醇水平平均降低27% (P〈0. 01)，以及趋向恢复到 正常饮食胆固醇水平降低平均44% (P〈0. 01)(图9)。
[0144] 参考文献
[0145] 1. Grundy SM, Cleeman JI,Merz CNB, Brewer, Jr, HB, Clark LT, Hunninghake DB，Pasternak RC，Smith，Jr，SC，Stone NJ(2QQ4). Implications of Recent ClinicalTrials for the National Cholesterol Education Program Adult Treatment Panel IIIGuidelines. Circulation 110,227-239.
[0146] 2. Abifadel M, Varret M, Rabes J, Allard D, Ouguerram K,Devillers M, Cruaud C,Benjannet S, Wickham L,Erlich D, DerreA,Villeger L,Farnier M,Beucler I，Bruckert E，Chambaz J，Chanu B，Lecerf J，Luc G，Moulin P, Weissenbach J，Prat A, Krempf M, Junien C, Seidah N,Boileau C (2003). Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet 34, 154-156.
[0147] 3. Pisciotta L，Priore Oliva C，Cefalu AB，Noto D，Bellocchio A，Fresa R，Cantafora A，Patel D，Averna M，Tarugi P，Calandra S,Bertolini S (2006). Additive effect of mutations in LDLR and PCSK9genes on the phenotype of familial hypercholesterolemia. Atherosclerosis 186, 433-440.
[0148] 4. Maxwell K, Breslow J(2004). Adenoviral-mediated expression of PCSK9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci USA 101，7100-7105.
[0149] 5. Ben jannet S，Rhainds D, Essalmani R, Mayne J, Wickham L，Jin ff, Asselin M, Hamel in J, Varret M，Allard D, Trillard M，Abifadel M，Tebon A, Attie AD，Rader DJ,Boileau C,Brissette L, Chretien M, Prat A, Seidah NG(2004). NARC-l/PCSK9and its natural mutants:zymogen cleavage and effects on the low density lipoprotein(LDL)receptor and LDL cholesterol. J Biol Chem 279,48865-48875.
[0150] 6. Cohen J, Pertsemlidis A, Kotowski I, Graham R, Garcia C, Hobbs H(2005). Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nature Genetics 37, 161-165.
[0151] 7. Rashid S，Curtis D，Garuti R，Anderson N，Bashmakov Y，Ho Y，Hammer H，Moon Y，Horton J(2005). Decreased plasma cholesterol and hypersensitivity to statins in mice lacking PCSK9.Proc Natl Acad Sci USA 102,5374-5379.
[0152] 8. Zhao Z, Tuakli-ffosornu Y，Lagace T，Kinch L，Grishin N，Horton J，Cohen J，Hobbs H(2006). Molecular Characterization of Loss-of-Function Mutations in PCSK9 and Identification of a Compound Heterozygote. Am J Human Genetics 79, 514-523.
[0153] 9. Benjannet S，Rhainds D，Hamelin J，Nassoury N，Seidah NG(2006) ? The proprotein convertase PCSK9 is inactivated by furin and/or PC5/6A:functional consequences of natural mutations and post-translational modifications. J Biol Chem 281，30561-30572.
[0154] 10. Li J，Tumanut C，Gavigan J_A，Huang W_J，Hampton EN，Tumanut R，Suen KF, Trauger Jff, Spraggon G,Lesley SA,Liau G, Yowe D, Harris JL (2007). Secreted PCSK9 promotes LDL receptor degradation independently of proteolytic activity. Biochem J 406, 203-207.
[0155] 11. McNutt MC, Lagace TA, Horton JD(2007). Catalytic activity is not required for secreted PCSK9 to reduce low density lipoprotein receptors in HepG2 cells. J Biol Chem 282,20799-20803.
[0156] 12. Zhang D-ff, Lagace TA,Garuti R, Zhao Z, McDonald M, Horton JD, Cohen JC，Hobbs HH(2007). Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem 282, 18602-18612.
[0157] 13. Kwon HJ, Lagace TA, McNutt MC, Jay D. Horton JD, Deisenhofer J(2008). Molecular basis for LDL receptor recognition by PCSK9. Proc Natl Acad Sci USA105, 1820 - 5.
[0158] 14. Bottomley MJ,Cirillo A, Orsatti L, Ruggeri L, Fisher TS, Santoro JC，Cummings RT，Cubbon RM,Lo Surdo P，Calzetta A，Noto A, Baysarowich J，Mattu M，Talamo F，De Francesco R, Sparrow CP，Sitlani A,CarflA (2009).Structural andbiochemical characterization of the wild type PCSK9/EGF(AB)complex and natural familial hypercholesterolemia mutants. J Biol Chem 284, 1313-1323.
[0159] 15. Seidah NG(2009) ? PCSK9 as a therapeutic target of dyslipidemia. Expert Opin Ther Targets 13, 19-28.
[0160] 16. Graham MJ, Lemonidis KM, Whipple CP,