Iwakubo Masayuki, Takami Atsuya, Okada Yuji, Kawata Takehisa, Tagami Yoshimichi, Sato Motoko, Sugiyama Terumi, Fukushima Kayoko, Taya Shinichiro, Amano Mutsuki, Kaibuchi Kozo, Iijima Hiroshi
Pharmaceutical Research Laboratories, Kirin Brewery Co. Ltd., 3 Miyahara-cho, Takasaki-shi, Gunma 370-1295, Japan.
Bioorg Med Chem. 2007 Jan 15;15(2):1022-33. doi: 10.1016/j.bmc.2006.10.028. Epub 2006 Oct 18.
The structure-activity relationship of Rho kinase inhibitors bearing an isoquinoline scaffold was studied. N-(1-Benzyl-3-pyrrolidyl)-N-(5-isoquinolyl)amine analogues were optimized with respect to their inhibitory potencies for the enzyme and for chemotaxis. The potent analogues were further evaluated by an ex vivo test in which the selected compounds were orally administered to rats, and the Rho kinase inhibitory potency observed in the rat serum was evaluated 3h after the administration. Compound 23g showed a high level of Rho kinase inhibitory activity in the rat serum and was stable in an in vitro metabolic test using a microsomal cytochrome preparation. The (R)-isomer of 23g displayed a higher level of inhibitory potency than the (S)-isomer in a cell-free kinase assay and in the cell migration assay (IC(50)(ENZ)=25 nM and IC(50)(MCP)=1 microM). The (R)-isomer successfully inhibited the phosphorylation of MBS (myosin-binding subunit) in cells.
研究了具有异喹啉骨架的Rho激酶抑制剂的构效关系。对N-(1-苄基-3-吡咯烷基)-N-(5-异喹啉基)胺类似物在酶抑制活性和趋化性方面进行了优化。通过体内试验进一步评估了有效的类似物，在该试验中，将选定的化合物口服给予大鼠，并在给药3小时后评估大鼠血清中观察到的Rho激酶抑制活性。化合物23g在大鼠血清中表现出高水平的Rho激酶抑制活性，并且在使用微粒体细胞色素制剂的体外代谢试验中稳定。在无细胞激酶试验和细胞迁移试验中，23g的(R)-异构体比(S)-异构体表现出更高水平的抑制活性(IC(50)(ENZ)=25 nM和IC(50)(MCP)=1 microM)。(R)-异构体成功抑制了细胞中MBS(肌球蛋白结合亚基)的磷酸化。
