- Invention of MK-8262, a Cholesteryl Ester Transfer Protein (CETP) Inhibitor Backup to Anacetrapib with Best-in-Class Properties ()
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Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.
- Vachal, Petr,Duffy, Joseph L.,Campeau, Louis-Charles,Amin, Rupesh P.,Mitra, Kaushik,Murphy, Beth Ann,Shao, Pengcheng P.,Sinclair, Peter J.,Ye, Feng,Katipally, Revathi,Lu, Zhijian,Ondeyka, Debra,Chen, Yi-Heng,Zhao, Kake,Sun, Wanying,Tyagarajan, Sriram,Bao, Jianming,Wang, Sheng-Ping,Cote, Josee,Lipardi, Concetta,Metzger, Daniel,Leung, Dennis,Hartmann, Georgy,Wollenberg, Gordon K.,Liu, Jian,Tan, Lushi,Xu, Yingju,Chen, Qinghao,Liu, Guiquan,Blaustein, Robert O.,Johns, Douglas G.
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supporting information
p. 13215 - 13258
(2021/09/02)
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- Preparation method of Anacetrapib
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The invention provides a preparation method of Anacetrapib. The method includes: firstly subjecting a compound 1 to ylide reaction to obtain olefin, and then carrying out epoxidation to obtain a compound 2; then, reacting the compound 2 with a compound 3 in a solvent to prepare a compound 4, finally subjecting the compound 4 to condensation reaction to obtain a compound 5, and conducting deprotection cyclization on the compound 5 so as to obtain a compound 6 Anacetrapib. The operation method provided by the invention is simple, has low requirement for water in the reaction system, is low in process cost, and is suitable for industrial application.
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Paragraph 0041; 0053; 0054
(2017/08/28)
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- Preparation method of Anacetrapib
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The invention relates to a preparation method of a compound represented by the formula (I). The preparation method comprises the following steps: (1) reacting 2-chloro-5-trifluoromethyl-aniline (II) with (4-fluoro-5-isopropyl-2-methoxyphenyl)boric acid (III) to obtain 2-(4-fluoro-5-isopropyl-20methoxyphenyl)-5-trifluoromethyl-aniline (formula IV); (2) reacting the compound (formula IV) with tert-butyl nitrite, acetaldehyde, and alkalis to obtain 2-(4-fluoro-5-isopropyl-2-methoxyphenyl)-5-trifluoromethyl-benzyl alcohol (formula V); (3) reacting the compound (formula V) with a halogenation reagent, and then adding (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidine-2-one (VI) into the reaction mixture to carry out reactions so as to obtain (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isoproypyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidine-2-one represented by the formula (I), namely Anacetrapib.
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- CATALYST AND METHOD FOR PRODUCING OPTICALLY ACTIVE ANTI-1,2-NITROALKANOL COMPOUND
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A catalyst, which is obtained by mixing a compound expressed by the following Structural Formula (1), a nitroalkane compound, a neodymium-containing compound, a sodium-containing compound, and a carbon structure:
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- PROCESS FOR PREPARATION OF ANACETRAPIB AND INTERMEDIATES THEREOF
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The present invention relates to a novel process for the preparation of anacetrapib. The present invention also relates to novel intermediate or its salt and its use in the preparation of anacetrapib.
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- Process for a CETP Inhibitor
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An efficient process is disclosed for producing the compound of formula I, which is the CETP inhibitor anacetrapib, which raises HDL-cholesterol and reduces LDL-cholesterol in human patients and may be effective for treating or reducing the risk of developing atherosclerosis:
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- SYNTHESIS OF INTERMEDIATES FOR PREPARING ANACETRAPIB AND DERIVATIVES THEREOF
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The present invention relates to the field of organic chemistry, more specifically to the synthesis of intermediate compounds which can be used in the synthesis of pharmaceutically active agents such as anacetrapib or derivatives thereof.
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- Self-assembling neodymium/sodium heterobimetallic asymmetric catalyst confined in a carbon nanotube network
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Confined cat works better: A self-assembling heterobimetallic catalyst, comprised of a Nd/Na/amide ligand confined in an entangled multiwalled carbon nanotube (MWNT) network, outperforms the unconfined catalyst in anti-selective catalytic asymmetric nitroaldol reactions. The confined catalyst could be used repeatedly through simple filtration, and was applied to a concise enantioselective synthesis of anacetrapib. Copyright
- Ogawa, Takanori,Kumagai, Naoya,Shibasaki, Masakatsu
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p. 6196 - 6201
(2013/07/19)
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- PROCESS FOR A CETP INHIBITOR
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An efficient process is disclosed for producing the compound of formula I, which is the CETP inhibitor anacetrapib, which raises HDL-cholesterol and reduces LDL-cholesterol in human patients and may be effective for treating or reducing the risk of developing atherosclerosis:.
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- SYNTHESIS OF INTERMEDIATES FOR PREPARING ANACETRAPIB AND DERIVATIVES THEREOF
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The present invention relates to the field of organic chemistry, more specifically to the synthesis of intermediate compounds which can be used in the synthesis of pharmaceutically active agents such as anacetrapib or derivatives thereof.
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- Synthesis of intermediates for preparing anacetrapib and derivates thereof
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The present invention relates to the field of organic chemistry, more specifically to the synthesis of intermediate compounds which can be used in the synthesis of pharmaceutically active agents such as anacetrapib or derivatives thereof.
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- Synthesis of intermediates for preparing anacetrapib and derivates thereof
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The present invention relates to the field of organic chemistry, more specifically to the synthesis of intermediate compounds which can be used in the synthesis of pharmaceutically active agents such as anacetrapib or derivatives thereof.
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- SAR studies on the central phenyl ring of substituted biphenyl oxazolidinone-potent CETP inhibitors
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SAR studies of the substitution effect on the central phenyl ring of the biphenyl scaffold were carried out using anacetrapib (9a) as the benchmark. The results revealed that the new analogs with substitutions to replace trifluoromethyl (9a) had a significant impact on CETP inhibition in vitro. In fact, analogs with some small groups were as potent or more potent than the CF3 derivative for CETP inhibition. Five of these new analogs raised HDL-C significantly (>20 mg/dL). None of them however was better than anacetrapib in vivo. The synthesis and biological evaluation of these CETP inhibitors are described.
- Lu, Zhijian,Chen, Yi-Heng,Napolitano, Joann B.,Taylor, Gayle,Ali, Amjad,Hammond, Milton L.,Deng, Qiaolin,Tan, Eugene,Tong, Xinchun,Xu, Suoyu S.,Latham, Melanie J.,Peterson, Laurence B.,Anderson, Matt S.,Eveland, Suzanne S.,Guo, Qiu,Hyland, Sheryl A.,Milot, Denise P.,Chen, Ying,Sparrow, Carl P.,Wright, Samuel D.,Sinclair, Peter J.
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scheme or table
p. 199 - 203
(2012/02/16)
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- PRODRUGS OF OXAZOLIDINONE CETP INHIBITORS
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The compounds of Formula I are prodrugs of CETP inhibitors having a central oxazolidinone ring. The compounds cyclize by the elimination of HX to form an oxazolidinone ring after administration to a patient.
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Page/Page column 43
(2010/04/27)
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- POLYMER FORMULATIONS OF CETP INHIBITORS
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A pharmaceutical composition comprises (a) a CETP inhibiting compound, or a pharmaceutically acceptable salt thereof; (b) a concentration-enhancing polymer; and (c) optionally one or more surfactants; wherein the compound has the structure shown as Formula I below. The composition raises HDL-cholesterol and lowers LDL-cholesterol.
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Page/Page column 24
(2010/11/28)
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- PROCESS FOR SYNTHESIZING A CETP INHIBITOR
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An efficient process is disclosed for producing a compound that is an inhibitor of CETP. The last step of the process is the coupling of an oxazolidinone derivative with a biphenyl moiety to provide a compound of formula (I). In a specific embodiment of this synthesis, a crystalline product is produced which is characterized as a non-solvated crystalline polymorph.
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Page/Page column 11-12
(2010/11/25)
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- CETP INHIBITORS
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Compounds having the structures of Formula I, including pharmaceutically acceptable salts of the compounds, are CETP inhibitors, and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis: In the compounds of Formula I, B or R2 is a phenyl group which has an ortho aryl, heterocyclic, benzoheterocyclic or benzocycloalky substituent, and one other position on the 5-membered ring has an aromatic, heterocyclic, cycloalkyl, benzoheterocyclic or benzocycloalky substituent connected directly to the ring or attached to the ring through a -CH2-.
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Page/Page column 80
(2010/10/19)
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