Hagiwara D, Miyake H, Igari N, Karino M, Maeda Y, Fujii T, Matsuo M
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
J Med Chem. 1994 Jun 24;37(13):2090-9. doi: 10.1021/jm00039a022.
As an extension of our studies on discovering a novel substance P (SP) antagonist, we modified the previously reported dipeptide, N2-[N2-(1H-indol-3-ylcarbonyl)-L-lysyl]-N-methyl-N-(phenyl-methyl) -L- phenylalaninamide (2b). The lysine part in 2b was first optimized to a (2S,4R)-hydroxyproline derivative (3h), which is 2-fold more potent than 2b in [3H]SP binding assay using guinea pig lung membranes. Next we modified the 1H-indol-3-ylcarbonyl part in 3h. Introduction of a methyl group at the indole nitrogen enhanced the oral activity, while retaining the binding activity. Finally, we modified the phenylalanine part to culminate in the most potent compound 7k (FK888), which is a potent SP antagonist with NK1 selectivity as well as oral activity.
作为我们发现新型P物质（SP）拮抗剂研究的延伸，我们对先前报道的二肽N2-[N2-(1H-吲哚-3-基羰基)-L-赖氨酰]-N-甲基-N-(苯基甲基)-L-苯丙氨酰胺（2b）进行了修饰。首先将2b中的赖氨酸部分优化为(2S,4R)-羟基脯氨酸衍生物（3h），在使用豚鼠肺膜的[3H]SP结合试验中，其效力比2b高2倍。接下来，我们对3h中的1H-吲哚-3-基羰基部分进行了修饰。在吲哚氮上引入甲基增强了口服活性，同时保留了结合活性。最后，我们对苯丙氨酸部分进行修饰，最终得到了最有效的化合物7k（FK888），它是一种具有NK1选择性和口服活性的强效SP拮抗剂。
