Chen Ping, Doweyko Arthur M, Norris Derek, Gu Henry H, Spergel Steven H, Das Jagabundhu, Moquin Robert V, Lin James, Wityak John, Iwanowicz Edwin J, McIntyre Kim W, Shuster David J, Behnia Kamelia, Chong Saeho, de Fex Henry, Pang Suhong, Pitt Sydney, Shen Ding Ren, Thrall Sara, Stanley Paul, Kocy Octavian R, Witmer Mark R, Kanner Steven B, Schieven Gary L, Barrish Joel C
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.
J Med Chem. 2004 Aug 26;47(18):4517-29. doi: 10.1021/jm030217e.
A series of novel anilino 5-azaimidazoquinoxaline analogues possessing potent in vitro activity against p56Lck and T cell proliferation have been discovered. Subsequent SAR studies led to the identification of compound 4 (BMS-279700) as an orally active lead candidate that blocks the production of proinflammatory cytokines (IL-2 and TNFalpha) in vivo. In addition, an expanded set of imidazoquinoxalines provided several descriptive QSAR models highlighting the influence of significant steric and electronic features. The H-bonding (Met319) contribution to observed binding affinities within a tightly congeneric series was found to be significant.
已发现一系列对p56Lck和T细胞增殖具有强大体外活性的新型苯胺基5-氮杂咪唑并喹喔啉类似物。随后的构效关系研究确定化合物4（BMS-279700）为口服活性先导候选物，其可在体内阻断促炎细胞因子（IL-2和TNFα）的产生。此外，一组扩展的咪唑并喹喔啉提供了几个描述性的定量构效关系模型，突出了显著的空间和电子特征的影响。发现氢键（Met319）对紧密同系物系列中观察到的结合亲和力的贡献很大。
