Design, Synthesis and Biological Evaluation of N,N-Substituted Amine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors

被引：0
作者：
Wang, Xinran [1 ]
Hao, Lijuan [1 ]
Xu, Xuanqi [2 ]
Li, Wei [1 ]
Liu, Chunchi [1 ]
Zhao, Dongmei [1 ]
Cheng, Maosheng [1 ]
机构：
[1] Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Liaoning, Peoples R China
[2] Univ Wisconsin, Dept Chem, Madison, WI 53715 USA
来源：
MOLECULES | 2017年 / 22卷 / 10期
基金：
中国国家自然科学基金;
关键词：
synthesis; N; N-substituted amine derivatives; CETP inhibitors; HDL-C; CORONARY-HEART-DISEASE; RANDOMIZED CLINICAL-TRIAL; HIGH-RISK; LDL CHOLESTEROL; HDL CHOLESTEROL; CETP INHIBITOR; DOUBLE-BLIND; TORCETRAPIB; DALCETRAPIB; ATHEROSCLEROSIS;
D O I：
10.3390/molecules22101658
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
N,N-Substituted amine derivatives were designed by utilizing a bioisosterism strategy. Consequently, twenty-two compounds were synthesized and evaluated for their inhibitory activity against CETP. Structure-activity relationship (SAR) studies indicate that hydrophilic groups at the 2-position of the tetrazole and 3,5-bistrifluoromethyl groups on the benzene ring provide important contributions to the potency. Among these compounds, compound 17 exhibited excellent CETP inhibitory activity (IC50 = 0.38 +/- 0.08 mu M) in vitro. Furthermore, compound 17 was selected for an in vitro metabolic stability study.
引用
收藏
页数：15
相关论文
共 24 条
  • [1] HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events
    Barter, Philip
    Gotto, Antonio M.
    LaRosa, John C.
    Maroni, Jaman
    Szarek, Michael
    Grundy, Scott M.
    Kastelein, John J. P.
    Bittner, Vera
    Fruchart, Jean-Charles
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2007, 357 (13) : 1301 - 1310
  • [2] Effects of torcetrapib in patients at high risk for coronary events
    Barter, Philip J.
    Caulfield, Mark
    Eriksson, Mats
    Grundy, Scott M.
    Kastelein, John J. P.
    Komajda, Michel
    Lopez-Sendon, Jose
    Mosca, Lori
    Tardif, Jean-Claude
    Waters, David D.
    Shear, Charles L.
    Revkin, James H.
    Buhr, Kevin A.
    Fisher, Marian R.
    Tall, Alan R.
    Brewer, Bryan
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2007, 357 (21) : 2109 - 2122
  • [3] Hugh Sinclair Lecture: The regulation and remodelling of HDL by plasma factors
    Barter, PJ
    [J]. ATHEROSCLEROSIS SUPPLEMENTS, 2002, 3 (04) : 39 - 47
  • [4] Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial
    Bots, Michiel L.
    Visseren, Frank L.
    Evans, Gregory W.
    Riley, Ward A.
    Revkin, James H.
    Tegeler, Charles H.
    Shear, Charles L.
    Duggan, William T.
    Vicari, Ralph M.
    Grobbee, Diederick E.
    Kastelein, John J.
    [J]. LANCET, 2007, 370 (9582) : 153 - 160
  • [5] Effects of anacetrapib on plasma lipids in specific patient subgroups in the DEFINE (Determining the Efficacy and Tolerability of CETP INhibition with AnacEtrapib) trial
    Brinton, Eliot A.
    Kher, Uma
    Shah, Sukrut
    Cannon, Christopher P.
    Davidson, Michael
    Gotto, Antonio M.
    Ashraf, Tanya B.
    Sisk, Christine McCrary
    Dansky, Hayes
    Mitchel, Yale
    Barter, Philip
    [J]. JOURNAL OF CLINICAL LIPIDOLOGY, 2015, 9 (01) : 65 - 71
  • [6] Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol
    Brousseau, ME
    Schaefer, EJ
    Wolfe, ML
    Bloedon, LT
    Digenio, AG
    Clark, RW
    Mancuso, JP
    Rader, DJ
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2004, 350 (15) : 1505 - 1515
  • [7] Safety of Anacetrapib in Patients with or at High Risk for Coronary Heart Disease.
    Cannon, Christopher P.
    Shah, Sukrut
    Dansky, Hayes M.
    Davidson, Michael
    Brinton, Eliot A.
    Gotto, Antonio M., Jr.
    Stepanavage, Michael
    Liu, Sherry Xueyu
    Gibbons, Patrice
    Ashraf, Tanya B.
    Zafarino, Jennifer
    Mitchel, Yale
    Barter, Philip
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2010, 363 (25) : 2406 - 2415
  • [8] Cholesteryl ester transfer protein: at the heart of the action of lipid-modulating therapy with statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors
    Chapman, M. John
    Le Goff, Wilfried
    Guerin, Maryse
    Kontush, Anatol
    [J]. EUROPEAN HEART JOURNAL, 2010, 31 (02) : 149 - 164
  • [9] A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coronary heart disease in the elderly
    Curb, JD
    Abbott, RD
    Rodriguez, BL
    Masaki, K
    Chen, R
    Sharp, DS
    Tall, AR
    [J]. JOURNAL OF LIPID RESEARCH, 2004, 45 (05) : 948 - 953
  • [10] A review of CETP and its relation to atherosclerosis
    de Grooth, GJ
    Klerkx, AHEM
    Stroes, ESG
    Stalenhoef, AFH
    Kastelein, JJP
    Kuivenhoven, JA
    [J]. JOURNAL OF LIPID RESEARCH, 2004, 45 (11) : 1967 - 1974
123