Hodge C N, Aldrich P E, Wasserman Z R, Fernandez C H, Nemeth G A, Arvanitis A, Cheeseman R S, Chorvat R J, Ciganek E, Christos T E, Gilligan P J, Krenitsky P, Scholfield E, Strucely P
Department of Chemical and Physical Sciences, DuPont Pharmaceuticals Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880-0500,
J Med Chem. 1999 Mar 11;42(5):819-32. doi: 10.1021/jm980223o.
As described in the preceding paper (Arvanitis et al. J. Med. Chem. 1999, 42), anilinopyrimidines I were identified as potent antagonists of corticotropin-releasing hormone-1 receptor (CRH1-R, also referred to as corticotropin-releasing factor, CRF1-R). Our next goal was to understand the receptor-bound conformation of the antagonists and to use this information to help guide preclinical optimization of the series and to develop new leads. Since receptor structural information was not available, we assumed that these small, high-affinity antagonists would tend to bind in conformations at or energetically close to their global minima and that rigid analogues that maintained the important stereoelectronic features of the bound anilinopyrimidine would also bind tightly. Conformational preferences and barriers to rotation of the anilinopyrimidines were determined by semiempirical methods, and X-ray and variable-temperature NMR spectroscopy provided experimental results that correlated well with calculated structures. Using these data, a key dihedral angle was constrained to design fused-ring analogues, substituted N-arylpyrrolopyridines II, synthesis of which provided CRH1 receptor antagonists with potency equal to that of the initial congeneric leads (Ki = 1 nM) and which closely matched the conformation held by the original compound, as determined by crystallography. In addition to providing a useful template for further analogue synthesis, the study unequivocally determined the active conformation of the anilinopyrimidines. Theoretical and spectroscopic studies, synthesis, and receptor binding data are presented.
如前文所述（阿尔瓦尼蒂斯等人，《药物化学杂志》，1999年，第42卷），苯胺基嘧啶I被鉴定为促肾上腺皮质激素释放激素-1受体（CRH1-R，也称为促肾上腺皮质激素释放因子，CRF1-R）的强效拮抗剂。我们的下一个目标是了解拮抗剂与受体结合的构象，并利用这些信息来指导该系列药物的临床前优化以及开发新的先导化合物。由于无法获得受体的结构信息，我们推测这些小的高亲和力拮抗剂倾向于以接近其全局最低点的构象或能量上与之接近的构象结合，并且保持结合态苯胺基嘧啶重要立体电子特征的刚性类似物也会紧密结合。通过半经验方法确定了苯胺基嘧啶的构象偏好和旋转障碍，X射线和变温核磁共振光谱提供的实验结果与计算结构相关性良好。利用这些数据，通过限制一个关键二面角来设计稠环类似物，即取代的N-芳基吡咯并吡啶II，其合成得到的CRH1受体拮抗剂的效力与最初的同系先导化合物相当（Ki = 1 nM），并且通过晶体学确定其与原始化合物的构象紧密匹配。除了为进一步的类似物合成提供有用的模板外，该研究还明确确定了苯胺基嘧啶的活性构象。文中展示了理论和光谱研究、合成以及受体结合数据。
