Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of N-[(1R)-1-(3-Cyclopropoxy-4-fluorophenyl)-1[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)benzamide (BMS-795311)

Qiao Jennifer X.; Wang Tammy C.; Adam Leonard P.; Chen Alice Ye A.; Taylor David S.; Yang Richard Z.; Zhuang Shaobin; Sleph Paul G.; Li Julia P.; Li Danshi; Yin Xiaohong; Chang Ming; Chen Xue-Qing; Shen Hong; Li Jianqing; Smith Daniel; Wu Dauh-Rurng; Leith Leslie; Harikrishnan Lalgudi S.; Kamau Muthoni G.; Miller Michael M.; Bilder Donna; Rampulla Richard; Li Yi-Xin; Xu Carrie; Lawrence R. Michael; Poss Michael A.; Levesque Paul; Gordon David A.; Huang Christine S.; Finlay Heather J.; Wexler Ruth R.; Salvati Mark E.

首页> 外文期刊>Journal of Medicinal Chemistry >Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of N-[(1R)-1-(3-Cyclopropoxy-4-fluorophenyl)-1[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)benzamide (BMS-795311)

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Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of N-[(1R)-1-(3-Cyclopropoxy-4-fluorophenyl)-1[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)benzamide (BMS-795311)

机译：三苯基乙胺衍生物作为胆固醇酯转移蛋白抑制剂：N-[（1R）-1-（3-环丙氧基-4-氟苯基）-1 [3-氟-5-（1,1,2,2-四氟乙氧基）苯基的发现] -2-苯基乙基] -4-氟-3-（三氟甲基）苯甲酰胺（BMS-795311）

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Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.

机译：胆固醇酯转移蛋白（CETP）抑制剂可提高动物和人类的HDL-C，并可能通过增强胆固醇逆向转运（RCT）来抗动脉粥样硬化。在本文中，我们描述了导致最优化和口服CETP抑制剂的一系列三苯乙胺（TPE）脲和酰胺的优化工作。化合物10g是一种有效的CETP抑制剂，在人类CETP / apoB-100双转基因小鼠中，口服剂量为1 mg / kg时，最大程度地抑制了胆固醇酯（CE）的转移活性，并增加了与Torcetrapib（1）相当的HDL胆固醇含量和大小。中等脂肪的仓鼠。与具有1的脱靶负债相反，在大鼠遥测研究中，在10g时未观察到血压升高，在H295R细胞中未检测到醛固酮合酶（CYP11B2）升高。根据其临床前概况，将化合物10g推进临床前安全性研究。

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《Journal of Medicinal Chemistry》 |2015年第22期|共17页
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Qiao Jennifer X.; Wang Tammy C.; Adam Leonard P.; Chen Alice Ye A.; Taylor David S.; Yang Richard Z.; Zhuang Shaobin; Sleph Paul G.; Li Julia P.; Li Danshi; Yin Xiaohong; Chang Ming; Chen Xue-Qing; Shen Hong; Li Jianqing; Smith Daniel; Wu Dauh-Rurng; Leith Leslie; Harikrishnan Lalgudi S.; Kamau Muthoni G.; Miller Michael M.; Bilder Donna; Rampulla Richard; Li Yi-Xin; Xu Carrie; Lawrence R. Michael; Poss Michael A.; Levesque Paul; Gordon David A.; Huang Christine S.; Finlay Heather J.; Wexler Ruth R.; Salvati Mark E.;
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1. Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of N-[(1R)-1-(3-Cyclopropoxy-4-fluorophenyl)-1[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)benzamide (BMS-795311) [J] . Qiao Jennifer X., Wang Tammy C., Adam Leonard P., Journal of Medicinal Chemistry . 2015,第22期

机译：三苯基乙胺衍生物作为胆固醇酯转移蛋白抑制剂：N-[（1R）-1-（3-环丙氧基-4-氟苯基）-1 [3-氟-5-（1,1,2,2-四氟乙氧基）苯基的发现] -2-苯基乙基] -4-氟-3-（三氟甲基）苯甲酰胺（BMS-795311）
2. Design, Synthesis, and Biological Evaluation of (2R, αS)-3,4-Dihydro-2-[3-(1,1,2,2-tetrafluoroet_hoxy)phenyl]-5-[3-(trifluoromethoxy)-phenyl]-α-(trifluoromethyl)-1(2H)-quinolineethanol as Potent and Orally Active Cholesteryl Ester Transfer Protein Inhibitor [J] . Gee-Hong Kuo, Thomas Rano, Patricia Pelton, Journal of Medicinal Chemistry . 2009,第6期

机译：（2R，αS）-3,4-二氢-2- [3-（1,1,2,2-四氟乙氧基）苯基] -5- [3-（三氟甲氧基）-苯基]的设计，合成及生物学评价-α-（三氟甲基）-1（2H）-喹啉乙醇为强效和口服活性胆固醇酯转移蛋白抑制剂
3. Discovery of 2-(2-chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1H-[1,4]dioxino [2 ',3 ':3,4]benzo[1,2-d]imidazole-5-carboxamide as potent, selective and efficacious microsomal prostaglandin E-2 synthase-1 (mPGES-1) inhibitor [J] . Muthukaman Nagarajan, Deshmukh Sanjay, Sarode Neelam, Bioorganic and Medicinal Chemistry Letters . 2016,第24期

机译：发现了2-（2-氯-6-氟苯基）氨基）-N-（3-氟-5-（三氟甲基）苯基）-1-甲基-7,8-二氢-1H- [1,4]二恶英[ 2'，3'：3,4]苯并[1,2-d]咪唑-5-羧酰胺作为有效，选择性和有效的微粒体前列腺素E-2合酶-1（mPGES-1）抑制剂
4. Design Synthesis and Biological Evaluation of NN-Substituted Amine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors [O] . Xinran Wang, Lijuan Hao, Xuanqi Xu, 2017

机译：NN取代的胺衍生物作为胆固醇酯转移蛋白抑制剂的设计合成和生物学评价
5. Design, Synthesis and Biological Evaluation of N,N-Substituted Amine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors [O] . Xinran Wang, Lijuan Hao, Xuanqi Xu, 2017

机译：N，N-取代胺衍生物作为胆固醇酯转移蛋白抑制剂的设计，合成及生物学评价

Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of N-[(1R)-1-(3-Cyclopropoxy-4-fluorophenyl)-1[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)benzamide (BMS-795311)

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