Chand Pooran, Babu Y Sudhakar, Bantia Shanta, Rowland Scott, Dehghani Ali, Kotian Pravin L, Hutchison Tracy L, Ali Shoukath, Brouillette Wayne, El-Kattan Yahya, Lin Tsu-Hsing
BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake Drive, Birmingham, AL 35244, USA.
J Med Chem. 2004 Apr 8;47(8):1919-29. doi: 10.1021/jm0303406.
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-1' 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 (IC(50) = 0.015-0.080 microM) vs the neuraminidase A form, but modest activity (IC(50) = 3.0-9.2 microM) 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.
在进一步旨在鉴定有效且安全的流感神经氨酸酶抑制剂的研究中，我们合成了一系列多取代环戊烷酰胺衍生物。所制备的酰胺包括：由伯胺制备的14个N-取代烷基或芳烷基类型的实例、由仲胺制备的13个N,N-二取代烷基、芳烷基或取代烷基类型的实例以及由脂环族或取代脂环族仲胺制备的12个实例。这些在环上的1位和连接在3位的侧链上的1'位带有两个手性中心的化合物，对其抑制甲型和乙型流感神经氨酸酶的能力进行了测试。1-乙基丙酰胺、二乙酰胺、二丙酰胺和4-吗啉基酰胺对甲型神经氨酸酶显示出非常好的抑制活性（IC(50)=0.015 - 0.080 microM），但对乙型神经氨酸酶的活性适中（IC(50)=3.0 - 9.2 microM）。由于母体酰胺带有两个手性中心（C-1和C-1'），对三种较好的抑制剂以更高的非对映体纯度水平进行了测试。对应于1-(乙基)丙酰胺、二乙酰胺和二丙酰胺（在C-1'手性中心均具有相同构型）活性形式的非对映体，以及代表C-1'和C-1处活性形式的二乙酰胺的非对映体，从作为非对映体分离的前体中分离或合成得到。这些非对映体在神经氨酸酶抑制方面相对于母体非对映体混合物显示出一定的改善。还制备了最佳活性化合物二乙酰胺和二丙酰胺的1-羧基-1-羟基衍生物。这些化合物的活性不如没有1-羟基的化合物。在一项体内研究中，对来自1-羧基系列的二乙酰胺的C-1'活性异构体通过口服和鼻内给药在感染流感的小鼠中进行了测试，发现其仅在鼻内给药时非常有效，在低至0.1（mg/kg）/天的剂量下可防止体重减轻。
