Syntheses and neuraminidase inhibitory activity of multisubstituted cyclopentane amide derivatives
Syntheses and neuraminidase inhibitory activity of multisubstituted cyclopentane amide derivatives
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DOI：
10.1021/jm0303406
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发表时间：
2004-04-08
影响因子：
7.3
通讯作者：
Lin, TH
中科院分区：
文献类型：
--
作者：
Chand, P;Babu, YS;Lin, TH
在进一步的研究中，旨在确定有效和安全的流感神经氨酸酶抑制剂，我们合成了一系列多取代环戊烷酰胺衍生物。所制备的酰胺是由伯胺制备的N-取代的烷基或芳烷基类型的14个实例，由仲胺制备的N，N-二取代的烷基、芳烷基或取代的烷基类型的13个实例，和由脂环族或取代的脂环族仲胺制备的12个实例。测试了这些在环中的位置-1 '和连接在位置3的侧链中的位置-V带有两个手性中心的化合物抑制流感神经氨酸酶的A和B形式的能力。1-乙基丙基酰胺、二乙基酰胺、二丙基酰胺和4-吗啉基酰胺对神经氨酸酶A型显示出非常好的抑制活性（IC 50 = 0.015-0.080 μ M），但对神经氨酸酶B型显示出中等活性（IC 50 = 3.0-9.2 μ M）。由于母体酰胺具有两个手性中心（C-1和C-1 '），因此在较高水平的非对映体纯度下测试了三种较好的抑制剂。对应于1-（乙基）丙基酰胺、二乙基酰胺和二丙基酰胺的活性形式的非对映异构体（在C-1'手性中心处均具有相同构型）和代表在C-1'和C-1处的活性形式的二乙基酰胺的非对映异构体从作为非对映异构体分离的前体分离或合成。这些非对映异构体显示出比母体非对映异构体混合物在神经氨酸酶抑制方面的一些改善。还制备了最佳活性化合物二乙基酰胺和二丙基酰胺的1-羧基-1-羟基衍生物。这些化合物的活性不如不含1-羟基的化合物。在一项体内研究中，通过口服和鼻内给药在流感感染的小鼠中测试了1-羧基系列二乙酰胺的C-1'活性异构体，发现仅在低至0.1（mg/kg）/天的剂量下鼻内给药在预防体重减轻方面非常有效。
In further studies aimed toward identifying effective and safe inhibitors of influenza neuraminidases, we synthesized a series of multisubstituted cyclopentane amide derivatives. Amides prepared were 14 examples of N-substituted alkyl or aralkyl types from primary amines, 13 examples of the N,N-disubstituted alkyl, aralkyl, or substituted-alkyl type from secondary amines, and 12 examples from cycloaliphatic or substituted cycloaliphatic secondary amines. These compounds bearing two chiral centers, at position-1' in the ring and position-V in the side chain attached at position 3, were tested for their ability to inhibit A and B forms of influenza neuraminidase. The 1-ethylpropylamide, diethylamide, dipropylamide, and 4-morpholinylamide showed very good inhibitory activity (IC50 = 0.015-0.080 muM) vs the neuraminidase A form, but modest activity (IC50 = 3.0-9.2 muM) vs the neuraminidase B form. Since the parent amides bear two chiral centers (C-1 and C-1') three of the better inhibitors were tested at higher levels of diastereomeric purity. The diastereomers corresponding to the active forms of the 1-(ethyl)propylamide, the diethylamide, and the dipropylamide (all of the same configuration at the C-1' chiral center), and the diastereomer of the diethylamide representing the active form at both C-1' and C-1 were isolated or synthesized from precursors that were isolated as diastereomers. These diastereomers showed some improvement in neuraminidase inhibition over the parent diastereomeric mixtures. 1-Carboxy-1-hydroxy derivatives of the best active compounds, the diethylamide and the dipropylamide, were also prepared. These compounds were not as active as the compounds without the 1-hydroxy group. In an in vivo study, the C-1' active isomer of the diethylamide from the 1-carboxy series was tested in influenza-infected mice by oral and intranasal administration and found to be very effective only intranasally in preventing weight loss at doses as low as 0.1 (mg/kg)/day.