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Compd. n R X pIC50
Ca2+ Neginotropy
4 2 2-ClC6H4 N(CH3)2 8.1 7.5
5 2 2-ClC6H4 c-NC4H8 7.9 7.7
6 2 2-ClC6H4 c-N(CH2CH2)2O 7.8 7.5
7 2 2-ClC6H4 c-N(CH2CH2)2NCH3 8.0 7.9
8 2 2-ClC6H4 c-N(CH2CH2)2N-i-Pr 8.2 8.0
9 2 2-ClC6H4 c-N(CH2CH2)2NPh-4-F 7.9 7.3
10 2 2-ClC6H4 c-N(CH2CH2)2NCH2Ph-4-Cl 8.0 7.4
11 2 2-ClC6H4 6.4 7.1
12 2 2-ClC6H4 6.0 7.1
13 2 2-ClC6H4 6.8 7.4
14 2 2-ClC6H4 N(CH3)CH2Ph 7.4 7.3
15 2 2-ClC6H4 NHCH3 8.5 7.5
1 (R, S) 2 2-ClC6H4 NH2 8.1 7.2
1 S-(-) 2 2-ClC6H4 NH2 8.7 NT
1 R-(+) 2 2-ClC6H4 NH2 5.8 NT
16 3 2-ClC6H4 N(CH3)2 8.6 8.6
17 3 2-ClC6H4 c-N(CH2CH2)2NCH3 8.4 8.2
18 2 2-Thienyl N(CH3)2 6.9 6.6
19 2 2-Pyridinyl N(CH3)2 6.1 6.0
20 2 1-Naphthyl N(CH3)2 7.1 7.7
21 2 2-CF3C6H4 N(CH3)2 7.4 7.6
22 2 2-NO2C6H4 N(CH3)2 8.0 7.1
23 2 2-CH3C6H4 NHCH3 7.2 7.2
24 2 2-OCH3C6H4 NHCH3 7.2 7.1
25 2 2-Cl-6-FC6H3 NHCH3 7.9 7.6
26 2 C6H5 NH2 6.8 6.2
27 2 2-FC6H4 NH2 7.8 6.6
28 2 3-ClC6H4 NH2 7.9 6.6
29 2 2, 3-Cl2C6H3 NH2 7.9 6.6
30 2 2-Cl-3-CF3C6H3 NH2 8.5 7.3
31 2 4-ClC6H4 NH2 6.0 6.0
32 2 2-ClC6H4 N3 NT NT
33 2 C6H5 N3 NT NT
34 2 2-FC6H4 N3 NT NT
35 2 2, 3-Cl2C6H3 N3 NT NT
36 2 4-ClC6H4 N3 NT NT
37 2 2-ClC6H4 Phthalimido NT NT
38 2 3-ClC6H4 Phthalimido NT NT
39 2 2-Cl-3-CF3C6H3 Phthalimido NT NT
40 2 2-ClC6H4 NT NT
2 Nifedipine 8.4 7.5
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Structures and activity of 4-substituted phenyl-2-aminoalkyloxy-dihydropyridines. NT = not test

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Compd. n R X pIC50
Ca2+ Neginotropy
4 2 2-ClC6H4 N(CH3)2 8.1 7.5
5 2 2-ClC6H4 c-NC4H8 7.9 7.7
6 2 2-ClC6H4 c-N(CH2CH2)2O 7.8 7.5
7 2 2-ClC6H4 c-N(CH2CH2)2NCH3 8.0 7.9
8 2 2-ClC6H4 c-N(CH2CH2)2N-i-Pr 8.2 8.0
9 2 2-ClC6H4 c-N(CH2CH2)2NPh-4-F 7.9 7.3
10 2 2-ClC6H4 c-N(CH2CH2)2NCH2Ph-4-Cl 8.0 7.4
11 2 2-ClC6H4 6.4 7.1
12 2 2-ClC6H4 6.0 7.1
13 2 2-ClC6H4 6.8 7.4
14 2 2-ClC6H4 N(CH3)CH2Ph 7.4 7.3
15 2 2-ClC6H4 NHCH3 8.5 7.5
1 (R, S) 2 2-ClC6H4 NH2 8.1 7.2
1 S-(-) 2 2-ClC6H4 NH2 8.7 NT
1 R-(+) 2 2-ClC6H4 NH2 5.8 NT
16 3 2-ClC6H4 N(CH3)2 8.6 8.6
17 3 2-ClC6H4 c-N(CH2CH2)2NCH3 8.4 8.2
18 2 2-Thienyl N(CH3)2 6.9 6.6
19 2 2-Pyridinyl N(CH3)2 6.1 6.0
20 2 1-Naphthyl N(CH3)2 7.1 7.7
21 2 2-CF3C6H4 N(CH3)2 7.4 7.6
22 2 2-NO2C6H4 N(CH3)2 8.0 7.1
23 2 2-CH3C6H4 NHCH3 7.2 7.2
24 2 2-OCH3C6H4 NHCH3 7.2 7.1
25 2 2-Cl-6-FC6H3 NHCH3 7.9 7.6
26 2 C6H5 NH2 6.8 6.2
27 2 2-FC6H4 NH2 7.8 6.6
28 2 3-ClC6H4 NH2 7.9 6.6
29 2 2, 3-Cl2C6H3 NH2 7.9 6.6
30 2 2-Cl-3-CF3C6H3 NH2 8.5 7.3
31 2 4-ClC6H4 NH2 6.0 6.0
32 2 2-ClC6H4 N3 NT NT
33 2 C6H5 N3 NT NT
34 2 2-FC6H4 N3 NT NT
35 2 2, 3-Cl2C6H3 N3 NT NT
36 2 4-ClC6H4 N3 NT NT
37 2 2-ClC6H4 Phthalimido NT NT
38 2 3-ClC6H4 Phthalimido NT NT
39 2 2-Cl-3-CF3C6H3 Phthalimido NT NT
40 2 2-ClC6H4 NT NT
2 Nifedipine 8.4 7.5
), ArticleFig(id=1222466946394739476, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466821756805892, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Compd. Clearance/mL·min-1·kg-1 Vol. of distribution/L·kg-1 t1/2/h
1 11 25 30
Nifedipine 38 3.6 1.0
Nicardipine 37 3.5 1.0
), ArticleFig(id=1222466946487014168, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466821756805892, language=CN, label=Table 2, caption=

Pharmacokinetics of compound 1, nifedipine, and nicardipine

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Compd. Clearance/mL·min-1·kg-1 Vol. of distribution/L·kg-1 t1/2/h
1 11 25 30
Nifedipine 38 3.6 1.0
Nicardipine 37 3.5 1.0
), ArticleFig(id=1222466946566705947, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466821756805892, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Drug R1 R2 R3
Nimodipine (CH2)2OCH3 (CH3)2CH 3-NO2
Niludipine (CH2)2OEt EtO(CH2)2 3-NO2
Nitrendipine CH3 CH3CH2 3-NO2
Dorodipine CH2CH3 CH3CH2
Felodipine CH3 CH3CH2 2, 3-Cl2
Nisodipine CH3CH2 2-NO2
Manidipine CH3 3-NO2
Isradipine CH(CH3)2 CH3
Lacidipine CH2CH3 CH3CH2
Lercandipine CH3 3-NO2
), ArticleFig(id=1222466946688340768, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466821756805892, language=CN, label=Table 3, caption=

Names and structures of "dipine" calcium channel blockers

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Drug R1 R2 R3
Nimodipine (CH2)2OCH3 (CH3)2CH 3-NO2
Niludipine (CH2)2OEt EtO(CH2)2 3-NO2
Nitrendipine CH3 CH3CH2 3-NO2
Dorodipine CH2CH3 CH3CH2
Felodipine CH3 CH3CH2 2, 3-Cl2
Nisodipine CH3CH2 2-NO2
Manidipine CH3 3-NO2
Isradipine CH(CH3)2 CH3
Lacidipine CH2CH3 CH3CH2
Lercandipine CH3 3-NO2
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突破固有模式的氨氯地平的研制
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郭宗儒
药学学报 | 新药发现与研究实例简析 2019,54(6): 1141-1144
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药学学报 | 新药发现与研究实例简析 2019, 54(6): 1141-1144
突破固有模式的氨氯地平的研制
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郭宗儒
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  • 中国医学科学院、北京协和医学院药物研究所, 北京 100050
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出版时间: 2019-06-12 doi: 10.16438/j.0513-4870.2016-0864
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郭宗儒. 突破固有模式的氨氯地平的研制. 药学学报, 2019 , 54 (6) : 1141 -1144 . DOI: 10.16438/j.0513-4870.2016-0864
. Acta Pharmaceutica Sinica, 2019 , 54 (6) : 1141 -1144 . DOI: 10.16438/j.0513-4870.2016-0864
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新药创制是复杂的智力活动, 涉及科学研究、技术创造、产品开发和医疗效果等多维科技活动。每个药物都有自身的研发轨迹, 而构建化学结构是最重要的环节, 因为它涵盖了药效、药代、安全性和生物药剂学等多维性质。本栏目以药物化学视角, 对有代表性的药物的成功构建, 加以剖析和解读。
氨氯地平是跟随性研制的钙通道阻断剂, 却由于突破了2, 5位必须是二甲基的固有观念, 用胺烷基链替换其中一个甲基, 获得了良好的结构, 不仅改善了物化和药代性质, 还由于长链的末端氨基增添了与靶标的有益结合, 赋予分子以独特的性质, 例如增加了新的结合位点和在靶标处较长的驻留时间。分子设计的突破在药效、药代和物化性质等多方面取得了收获。(编者按)
1 研究背景和目标
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钙通道阻断剂“地平”类药物现已是熟知的降压药物。20世纪80年代研制氨氯地平(1, amlodipine)时, 上市或处于临床研究只是少数的几个如硝苯地平(2, nifedipine)和尼卡地平(3, nicardipine)等。地平类药物的结构特征是取代的二氢吡啶, 具有扩张外周血管平滑肌和舒张冠状动脉作用, 是降低血压和治疗心绞痛的常用药物。
辉瑞公司研发新的地平类钙阻断剂的目标是: ①药理作用强于或不低于硝苯地平的作用; ②口服生物利用度高于硝苯地平; ③降压作用的持续时间长, 口服一天一次; ④为提高溶解性和吸收性, 结构中最好含有助溶性基团。
当时上市和在研的钙阻断剂都是中性分子(二氢吡啶中的NH因p-π共轭, 孤电子对离域化而碱性很弱), 水溶性低而不易吸收。虽然尼卡地平的3位侧链有碱性氮原子, 溶解和吸收性较好, 但因肝脏的首过效应生物利用度仍比较低。
2 活性评价
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用大鼠主动脉螺旋条模型测定受试物体外活性。作用机制是钾离子造成细胞膜去极化, 钙离子导致主动脉条收缩, 受试物由于阻断电位敏感的L-型钙通道, 抑制了钙离子的过膜流量, 降低了血管收缩力, 通过测定张力的变化, 计算降低50%张力的化合物浓度, 取负对数(pIC50), 因而受试物的pIC50数值越大, 表明活性越高。另一模型是用Langendorff方法将含有受试物的Krebs-Henseleit液灌注豚鼠的离体心脏, 经连接的传感器测定心脏顶端的收缩力和心律, 计算化合物引起心脏收缩力降低25%所需的化合物浓度, 取负对数, 数值越小化合物越安全。
3 分子设计
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3.1 2位引入碱性侧链
为了增加化合物的水溶性和吸收性, 二氢吡啶环的2或3位可引入碱性基团, 然而尼卡地平的3位碱性侧链有不利的首过效应, 而按照文献披露的构效关系2位优选的应为甲基或小的烷基(Bossert F, MeGr H, Wehinger E. A new class of highly active calcium antagonists. Angew Chem Int Ed Eng, 1981, 20: 762-769), 似乎难以解决助溶基团的引入。但最后还是挑战了既有的构效关系, 在2位用胺烷基替换2-甲基, 通过变换3个位置的基团调整碱性和亲脂性, 优化活性和物化性质, 跟随性药物超越了已有的地平。表 1列出了合成的化合物和活性。
表 1的构效关系概括如下: ① 2位为二甲胺基乙氧甲基的化合物4活性与硝苯地平相近, 对心脏的脱靶作用所引起的负性收缩较弱, 选择性扩张血管作用为4倍[antilog(8.1-7.5)], 说明钙通道拮抗剂可以突破2位只能为甲基的限制, 碱性长链仍可保持活性。②碱性环状物5或6的活性和选择性与4相近, 但一些含有两个碱性氮原子的环状化合物如11~13对心脏的不良反应强于扩张外周血管作用, 因而是不利的。③化合物11的扩张血管活性高, 强于对心脏作用8倍, 因而选择性强。④将1的o-Cl变成m-Cl (28)或p-Cl (31), 活性显著下降, 尤其是对位取代是不可取的, 提示氯原子在2'位的重要性。⑤在邻位取代的基础上再作间位取代, 活性和选择性仍很高, 如化合物30。⑥ o-氯苯换成2-噻吩基、4-吡啶基或1-萘基(化合物18~20), 活性下降。⑦化合物16和17分别是在4和7的侧链中增加一个亚甲基, 活性显著下降。
3.2 高活性化合物的研究
化合物4、15、1和30呈现出高活性和选择性, 进而用静脉注射麻醉犬评价, 测定对冠状动脉和外周血管的血流量, 结果表明这4个化合物都呈现出剂量依赖性的降低冠脉和外周血管阻力的作用。尤其是化合物1, 灌胃清醒的肾型高血压犬, 表现出剂量依赖性的降压作用, 持续时间长于硝苯地平。
3.3 候选化合物的药代动力学
化合物1对于冠脉和外周血管呈现高活性和高选择性, 进而研究了犬的药代动力学性质。口服给药的生物利用度接近100%, 血浆半衰期为30 h, 血浆清除率为11 mL·min-1·kg-1, 分布容积25 L·kg-1, 作为跟随性药物这些数据显著超越了上市和先行的地平, 表 2列出了化合物1与硝苯地平和尼卡地平的药代数据。
按照1的药代数据口服用药每日1次, 用药到第4日即达到恒态浓度, 血药浓度为单次用药的2倍, 因而可低剂量用药, 避免发生不良反应, 适于高血压患者长期服用。
3.4 氨氯地平及其光活体
化合物1由于良好的药效和药代行为被确定为候选化合物, 定名为氨氯地平(amlodipine), 以苯磺酸盐进入开发研究。氨氯地平在二氢吡啶的4位连接了2'-氯苯基, 2, 4, 5, 6位为不同的基团取代, 由于迫位氯原子的阻转效应, 造成分子的不对称性, 构成对映异构体, 经拆分得到光活体1[S-(-)]和1[R-(+)], 体外实验表明, 1S-(-)的活性为消旋体的2倍, 是1R-(+)的1 000倍(表 1), 因而S-氨氯地平作为优映体进一步开发。经三期临床研究证明是治疗高血压和心绞痛的良好口服药物, 于1989年首先在英国上市, 1993年在美国上市。
4 氨氯地平的作用机制
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氨氯地平是血管选择性的钙通道阻断剂。在心肌、血管和其他细胞上存在的钙通道, 当通道开启时钙流入细胞引起细胞收缩。氨氯地平阻断钙通道的打开, 干扰了上述过程, 使冠状动脉和外周动脉舒张, 缓解心肌缺血和降低血压。
3H标记的S-氨氯地平与大鼠心肌细胞膜温孵表明, 与钙通道结合的离解速率koff= 1.53×10-3 min-1, 5 h后复合物离解低于40%, 复合物的慢速离解是氨氯地平的长效作用的原因之一。此外, 氨氯地平与其他地平类药物不同的是, 除结合于二氢吡啶结合位点外, 还与苯烷胺和苯并硫氮䓬位点结合, 这可能与2位存在胺烷基链有关(Nayler WG, Gu XH. The unique binding properties of amlodipine: a long-acting calcium antagonist. J Human Hypertension, 1991, 5 (Suppl 1): 55-59)。
4-取代苯基二氢吡啶是地平类的共同结构, 研究表明, 二氢吡啶呈假船式构象, 苯环以直立键占据船头, 2'位氯原子的阻转效应迫使苯环平面与二氢吡啶船面呈垂直态排布, 构成稳定的构型。形成的光学异构体可被钙通道选择性地识别与结合, S-氨氯地平为临床应用优映体。图 1是氨氯地平的氨基被吗啉基磺酰后的化合物(41)的晶体结构的X-射线衍射图, 可以看出2位侧链的氧原子与二氢吡啶的1位NH形成分子内氢键, 固定了侧链的走向。
5 其他二氢吡啶类钙阻断剂
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表 3列出了氨氯地平上市前后地平类药物, 可以看出这些药物的化学结构都是在二氢吡啶环的2, 5的酯基和4位苯环取代基的变换, 2, 5-二甲基都维持不变, 而只有氨氯地平的2位含有胺烷基链。
2019年第54卷第6期
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doi: 10.16438/j.0513-4870.2016-0864
  • 首发时间：2026-01-26
  • 出版时间：2019-06-12
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2种不同金属材料的力学参数
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Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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