新型胆固醇吸收抑制剂的设计与合成
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摘要
本论文分为四章,论述新型依泽替米贝模拟物的设计与合成,并初步进行了体内抑制胆固醇吸收活性的研究。
第一章介绍研究开发胆固醇吸收抑制剂的意义、胆固醇吸收抑制剂依泽替米贝的研发过程以及依泽替米贝代替物的研究。本实验室通过改变抑制剂分子骨架设计结构新颖1,3-位对调依泽替米贝电子等排体和依泽替米贝与他汀类药物拼合物,体内活性研究结果表明1,3-位对调依泽替米贝电子等排体具有较好降低大鼠血清胆固醇的活性。
第二章在保留依泽替米贝重要结构片段的基础上设计并合成了C3-位螺环取代β-内酰胺为核结构的新型结构依泽替米贝三维结构模拟物,活性研究C3-位螺环取代β-内酰胺依泽替米贝模拟物具有较好的抑制胆固醇吸收活性,同时六元螺环活性好于五元螺环抑制剂分子。在此基础上分别设计并合成了β-内酰胺环C3-位不同结构的依泽替米贝模拟物研究C3-位构型对于活性的影响,同时设计并合成了C3-位六元螺环结构新颖的依泽替米贝模拟物。
第三章在保留依泽替米贝重要结构片段的基础上,选用非β-内酰胺杂环亚乙基脲和唑烷酮为抑制剂核构建新型骨架的依泽替米贝模拟物,分别考虑取代基的链接位置以及顺、反构型对于活性的影响。选择亚乙基脲为核依泽替米贝模拟物进行体内活性研究发现均具有较好的降低实验性高脂模型仓鼠血清中总胆固醇(TC)和低密度脂蛋白胆固醇(LDL-C)的活性,同时具有升高高密度脂蛋白(HDL-C)活性的作用。
第四章在保留活性重要片断和对活性有利代谢片段基础上,将1,3-位对调依泽替米贝电子等排体核结构进行变换得到以异吲哚酮为核结构的全新的依泽替米贝模拟物,通过活性研究发现其具有很好的降低实验性高脂模型仓鼠血清中总胆固醇(TC)和低密度脂蛋白胆固醇(LDL-C)活性。利用电子等排理论设计并合成了2,3-二取代异吲哚酮模拟物,为寻找新型结构胆固醇吸收抑制剂打下基础。
This dissertation is divided into four chapters. First, the importance of research and development of cholesterol absorption inhibitor, the development and mechanism of ezetimibe, as well as analogs of ezetimibe, were summarized to achieve full understanding of ezetimibe as a cholesterol absorption inhibitor. Then, based on the anti-hyper-cholesterolemia activity of re-organized analogs of ezetimibe and the merger of ezetimibe and statin, with retention of the important structural fragments of ezetimibe, novle scaffold analogs of ezetimibe were designed and synthesized, and the activities of some compouds to inhibit cholesterol absorption were studied. These novel backbone analogs of ezetimibe had the potential cholesterol absorption inhibition activity.
In chapter one, the background of cholesterol absorption inhibitor ezetimibe was summarized. Atherosclerotic coronary heart disease (CHD) is always a major concern in healthcare due to its high morbidity and mortality. The cholesterol absorption inhibitor ezetimibe inhibits the absorption of dietary or recycled cholesterol in the intestine and can be used either alone or in combination with a statin. The discovery of ezetimibe originated from a project for novel acylcoenzyme cholesterol acyltransferase (ACAT) inhibitors. A series of conformationally constrained azetidinone analogs were prepared to profile their potencies in vitro and in vivo. The subsequent extraordinarily challenging medicinal chemistry effort led to the discovery of SCH48461, the prototype azetidinone cholesterol absorption inhibitor. By pharmacokinetics study of SCH48461 and structural improvement of active metabolite, more active inhibitor ezetimibe was found. In the target and mechanistic study of ezetimibe, NPC1L1 was determined as the target of ezetimibe through the use of proteomics method, ezetimibe blocks the sterol-induced internaliztion of NPC1L1 to achieve the activity of cholesterol absorption inhibition.
Previous work on novel cholesterol absorption inhibitors in Bai Lab was also summerized. With the maximum retention of the functional groups that exist in ezetimibe, four individual isomers of backbone re-organized ezetimibe analogs were designed and synthesized. Their effects on the cholesterol levels in rat serum were evaluated by a high-cholesterol and high-fat diet feeding experiment. All the new analogs showed significant effect in lowering the levels of total cholesterol in serum. A potential dual inhibitor for exogenous absorption and endogenic synthesis of cholesterol was designed based on conjugation of theβ-lactam pharmacophore of ezetimibe and theδ-lactone pharmacophore of statins, the merger was found to lower total glucose (TG) level in rat serum via a high-cholesterol and high-fat feeding experiment. As the previous work suggests, the design of novel cholesterol absorption inhibitor will follow the methodology that the active functional side chains are rearranged on novel scaffold.
In Chapter two, with retention of important functional groups in ezetimibe and the core of re-organized backbone analogs was replaced by spiro-β-lactam, ezetimibe analogs 2-(3-(4-fluorophenyl)-3-hydroxypropyl)-3-(4-hydroxyphenyl)-2-azaspiro[3.5] nonane-1-one and 2-(3-(4-fluorophenyl)-3-hydroxypropyl)-3-(4-hydroxyphenyl)-2- azaspiro[3.4]octan-1-one were designed and synthesized. These analogs were found to lower total cholesterol (TC) and total glucose (TG) level in hamster serum via a high-cholesterol and high-fat feeding experiment. After four weeks of pre-feeding, total cholesterol (TC) lowering activity of spiro-β-lactam ezetimibe analogs were further improved, these analogs also will lower total cholesterol (TC) in the liver and total glucose (TG).
The SAR studies suggest the advantage of N-phenyl onβ-lactam analogs, thus the existence of C3-phenyl is crucial for the activity of re-organized backbone analogs. Also the replacement of fluorophenyl substitutedβ-lactam by spiro-β-lactam have significant improvements in lowering the levels of TC and LDL-C in serum. And 2-(3-(4-fluorophenyl)-3-hydroxypropyl)-3-(4-hydroxyphenyl)-2-azaspiro[3.5]nonane-1-one is more active than 2-(3-(4-fluorophenyl)-3-hydroxypropyl)-3-(4-hydroxyphenyl)-2-azaspiro[3.4] octan-1-one. After further analysis of N1 SAR ofβ-lactam CAI, we speculate that the plane of a planar-structure substituent would form a certain conformation with theβ-lactam plane, and this conformation was beneficial for the inhibiting activity. To verify this assumption, we have designed and synthesizedβ-lactams with different C3 configurations to study SAR, and search for potent structure. With introduction of hydrogen bond and charge factors on theβ-lactams, novel azaspiro[3.5]nonane-1-one ezetimibe analogs were designed and synthesized for SAR study of cholesterol absorption inhibition. As the previous work suggests, the design of novel cholesterol absorption inhibitor will follow the methodology that the active functional side chains are rearranged on novel scaffold.
In Chapter three, using the strategy as in chapter two, with retention of the important functional groups in ezetimibe, a series of non-β-lactam (imidazolidin-2-one and oxazolidinone) core ezetimibe analogs were designed and synthesized as cholesterol absorption inhibitors. Imidazolidin-2-one analogs were synthesized as follow: first the 1, 2-diamines were synthesized, followed by the transformation to imidazolidin-2-one core, alkylating the core with the alcohol fragment, and finally the deprotection of phenolic protecting group. Substituted oxazolidinones were synthesized through the reaction of benzyl and Boc-substituted aniline with benzaldehyde under n-butyl lithium, followed by alkylation with the alcohol fragment and deprotection of the phenolic protecting group. Imidazolidin-2-one analogs 1-(4-fluorophenyl)-3-(3-(4-fluorophenyl) -3-hydroxypropyl)-4-(4-hydroxyphenyl)imidazolidin-2-one and 3-(4-fluorophenyl)-1-(3- (4-fluorophenyl)-3-hydroxypropyl)-4-(4-hydroxyphenyl)imidazolidin-2-one showed significant effects in lowering the total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels in serum, as well as increasing high-density lipoprotein cholesterol (HDL-C) level. Also the imidazolidin-2-one core analogs were found to lower hamster liver total cholesterol (TC) and total glucose (TG).
In chapter four, using the strategy as the second and third chapters, with retention of the important functional groups in ezetimibe, novel backbone ezetimebe analogs with potential inhibitory activity was designed. Unlike in previous chapters, in which the cores have been reported in other cholesterol absorption inhibitors, the core discussed in this chapter has been changed fromβ-lactam to isoindolinone. And 2-(3-(4-fluorophenyl)-3-hydroxypropyl)-3- (4-hydroxyphenyl)isoindolin-1-one was designed and synthesized. It was found that 2, 3-disubstituted isoindolinone will lower total cholesterol (TC) 31%, low-density lipoprotein cholesterol (LDL-C) 30% and total glucose (TG) 9% in hamster serum via a high-cholesterol and high-fat feeding experiment. The isoindolinone-ezetimibe mimic has considerable inhibitory activity. After four weeks of pre-feeding, the total cholesterol (TC) lowering activity of 2, 3-disubstituted isoindolinone was further improved, as well as total cholesterol in the liver (TC). Analogs with other heterocyclic cores were designed and synthesized.
第一章介绍研究开发胆固醇吸收抑制剂的意义、胆固醇吸收抑制剂依泽替米贝的研发过程以及依泽替米贝代替物的研究。本实验室通过改变抑制剂分子骨架设计结构新颖1,3-位对调依泽替米贝电子等排体和依泽替米贝与他汀类药物拼合物,体内活性研究结果表明1,3-位对调依泽替米贝电子等排体具有较好降低大鼠血清胆固醇的活性。
第二章在保留依泽替米贝重要结构片段的基础上设计并合成了C3-位螺环取代β-内酰胺为核结构的新型结构依泽替米贝三维结构模拟物,活性研究C3-位螺环取代β-内酰胺依泽替米贝模拟物具有较好的抑制胆固醇吸收活性,同时六元螺环活性好于五元螺环抑制剂分子。在此基础上分别设计并合成了β-内酰胺环C3-位不同结构的依泽替米贝模拟物研究C3-位构型对于活性的影响,同时设计并合成了C3-位六元螺环结构新颖的依泽替米贝模拟物。
第三章在保留依泽替米贝重要结构片段的基础上,选用非β-内酰胺杂环亚乙基脲和唑烷酮为抑制剂核构建新型骨架的依泽替米贝模拟物,分别考虑取代基的链接位置以及顺、反构型对于活性的影响。选择亚乙基脲为核依泽替米贝模拟物进行体内活性研究发现均具有较好的降低实验性高脂模型仓鼠血清中总胆固醇(TC)和低密度脂蛋白胆固醇(LDL-C)的活性,同时具有升高高密度脂蛋白(HDL-C)活性的作用。
第四章在保留活性重要片断和对活性有利代谢片段基础上,将1,3-位对调依泽替米贝电子等排体核结构进行变换得到以异吲哚酮为核结构的全新的依泽替米贝模拟物,通过活性研究发现其具有很好的降低实验性高脂模型仓鼠血清中总胆固醇(TC)和低密度脂蛋白胆固醇(LDL-C)活性。利用电子等排理论设计并合成了2,3-二取代异吲哚酮模拟物,为寻找新型结构胆固醇吸收抑制剂打下基础。
This dissertation is divided into four chapters. First, the importance of research and development of cholesterol absorption inhibitor, the development and mechanism of ezetimibe, as well as analogs of ezetimibe, were summarized to achieve full understanding of ezetimibe as a cholesterol absorption inhibitor. Then, based on the anti-hyper-cholesterolemia activity of re-organized analogs of ezetimibe and the merger of ezetimibe and statin, with retention of the important structural fragments of ezetimibe, novle scaffold analogs of ezetimibe were designed and synthesized, and the activities of some compouds to inhibit cholesterol absorption were studied. These novel backbone analogs of ezetimibe had the potential cholesterol absorption inhibition activity.
In chapter one, the background of cholesterol absorption inhibitor ezetimibe was summarized. Atherosclerotic coronary heart disease (CHD) is always a major concern in healthcare due to its high morbidity and mortality. The cholesterol absorption inhibitor ezetimibe inhibits the absorption of dietary or recycled cholesterol in the intestine and can be used either alone or in combination with a statin. The discovery of ezetimibe originated from a project for novel acylcoenzyme cholesterol acyltransferase (ACAT) inhibitors. A series of conformationally constrained azetidinone analogs were prepared to profile their potencies in vitro and in vivo. The subsequent extraordinarily challenging medicinal chemistry effort led to the discovery of SCH48461, the prototype azetidinone cholesterol absorption inhibitor. By pharmacokinetics study of SCH48461 and structural improvement of active metabolite, more active inhibitor ezetimibe was found. In the target and mechanistic study of ezetimibe, NPC1L1 was determined as the target of ezetimibe through the use of proteomics method, ezetimibe blocks the sterol-induced internaliztion of NPC1L1 to achieve the activity of cholesterol absorption inhibition.
Previous work on novel cholesterol absorption inhibitors in Bai Lab was also summerized. With the maximum retention of the functional groups that exist in ezetimibe, four individual isomers of backbone re-organized ezetimibe analogs were designed and synthesized. Their effects on the cholesterol levels in rat serum were evaluated by a high-cholesterol and high-fat diet feeding experiment. All the new analogs showed significant effect in lowering the levels of total cholesterol in serum. A potential dual inhibitor for exogenous absorption and endogenic synthesis of cholesterol was designed based on conjugation of theβ-lactam pharmacophore of ezetimibe and theδ-lactone pharmacophore of statins, the merger was found to lower total glucose (TG) level in rat serum via a high-cholesterol and high-fat feeding experiment. As the previous work suggests, the design of novel cholesterol absorption inhibitor will follow the methodology that the active functional side chains are rearranged on novel scaffold.
In Chapter two, with retention of important functional groups in ezetimibe and the core of re-organized backbone analogs was replaced by spiro-β-lactam, ezetimibe analogs 2-(3-(4-fluorophenyl)-3-hydroxypropyl)-3-(4-hydroxyphenyl)-2-azaspiro[3.5] nonane-1-one and 2-(3-(4-fluorophenyl)-3-hydroxypropyl)-3-(4-hydroxyphenyl)-2- azaspiro[3.4]octan-1-one were designed and synthesized. These analogs were found to lower total cholesterol (TC) and total glucose (TG) level in hamster serum via a high-cholesterol and high-fat feeding experiment. After four weeks of pre-feeding, total cholesterol (TC) lowering activity of spiro-β-lactam ezetimibe analogs were further improved, these analogs also will lower total cholesterol (TC) in the liver and total glucose (TG).
The SAR studies suggest the advantage of N-phenyl onβ-lactam analogs, thus the existence of C3-phenyl is crucial for the activity of re-organized backbone analogs. Also the replacement of fluorophenyl substitutedβ-lactam by spiro-β-lactam have significant improvements in lowering the levels of TC and LDL-C in serum. And 2-(3-(4-fluorophenyl)-3-hydroxypropyl)-3-(4-hydroxyphenyl)-2-azaspiro[3.5]nonane-1-one is more active than 2-(3-(4-fluorophenyl)-3-hydroxypropyl)-3-(4-hydroxyphenyl)-2-azaspiro[3.4] octan-1-one. After further analysis of N1 SAR ofβ-lactam CAI, we speculate that the plane of a planar-structure substituent would form a certain conformation with theβ-lactam plane, and this conformation was beneficial for the inhibiting activity. To verify this assumption, we have designed and synthesizedβ-lactams with different C3 configurations to study SAR, and search for potent structure. With introduction of hydrogen bond and charge factors on theβ-lactams, novel azaspiro[3.5]nonane-1-one ezetimibe analogs were designed and synthesized for SAR study of cholesterol absorption inhibition. As the previous work suggests, the design of novel cholesterol absorption inhibitor will follow the methodology that the active functional side chains are rearranged on novel scaffold.
In Chapter three, using the strategy as in chapter two, with retention of the important functional groups in ezetimibe, a series of non-β-lactam (imidazolidin-2-one and oxazolidinone) core ezetimibe analogs were designed and synthesized as cholesterol absorption inhibitors. Imidazolidin-2-one analogs were synthesized as follow: first the 1, 2-diamines were synthesized, followed by the transformation to imidazolidin-2-one core, alkylating the core with the alcohol fragment, and finally the deprotection of phenolic protecting group. Substituted oxazolidinones were synthesized through the reaction of benzyl and Boc-substituted aniline with benzaldehyde under n-butyl lithium, followed by alkylation with the alcohol fragment and deprotection of the phenolic protecting group. Imidazolidin-2-one analogs 1-(4-fluorophenyl)-3-(3-(4-fluorophenyl) -3-hydroxypropyl)-4-(4-hydroxyphenyl)imidazolidin-2-one and 3-(4-fluorophenyl)-1-(3- (4-fluorophenyl)-3-hydroxypropyl)-4-(4-hydroxyphenyl)imidazolidin-2-one showed significant effects in lowering the total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels in serum, as well as increasing high-density lipoprotein cholesterol (HDL-C) level. Also the imidazolidin-2-one core analogs were found to lower hamster liver total cholesterol (TC) and total glucose (TG).
In chapter four, using the strategy as the second and third chapters, with retention of the important functional groups in ezetimibe, novel backbone ezetimebe analogs with potential inhibitory activity was designed. Unlike in previous chapters, in which the cores have been reported in other cholesterol absorption inhibitors, the core discussed in this chapter has been changed fromβ-lactam to isoindolinone. And 2-(3-(4-fluorophenyl)-3-hydroxypropyl)-3- (4-hydroxyphenyl)isoindolin-1-one was designed and synthesized. It was found that 2, 3-disubstituted isoindolinone will lower total cholesterol (TC) 31%, low-density lipoprotein cholesterol (LDL-C) 30% and total glucose (TG) 9% in hamster serum via a high-cholesterol and high-fat feeding experiment. The isoindolinone-ezetimibe mimic has considerable inhibitory activity. After four weeks of pre-feeding, the total cholesterol (TC) lowering activity of 2, 3-disubstituted isoindolinone was further improved, as well as total cholesterol in the liver (TC). Analogs with other heterocyclic cores were designed and synthesized.
引文
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