Kruse L I, Kaiser C, DeWolf W E, Finkelstein J A, Frazee J S, Hilbert E L, Ross S T, Flaim K E, Sawyer J L
Research and Development Division, Smith Kline & French Laboratories, King of Prussia, Pennsylvania 19406-0939.
J Med Chem. 1990 Feb;33(2):781-9. doi: 10.1021/jm00164a051.
Structure-activity relationships (SAR) were determined for novel multisubstrate inhibitors of dopamine beta-hydroxylase (DBH; EC 1.14.17.1) by examining the effects upon in vitro inhibitory potencies resulting from structural changes at the copper-binding region of inhibitor. Attempts were made to determine replacement groups for the thione sulfur atom of the prototypical inhibitor 1-(4-hydroxybenzyl)imidazole-2-thione described previously. The synthesis and evaluation of oxygen and nitrogen analogues of the soft thione group demonstrated the sulfur atom to be necessary for optimal activity. An additional series of imidazole-2-thione relatives was prepared in an effort to probe the relationship between the pKa of the ligand group and inhibitory potency. In vitro inhibitory potency was shown not to correlate with ligand pKa over a range of approximately 10 pKa units, and a rationale for this is advanced. Additional ligand modifications were prepared in order to explore bulk tolerance at the enzyme oxygen binding site and to determine the effects of substituting a six-membered ligand group for the five-membered imidazole-2-thione ligand.
通过研究抑制剂铜结合区域结构变化对体外抑制效力的影响，确定了多巴胺β-羟化酶（DBH；EC 1.14.17.1）新型多底物抑制剂的构效关系（SAR）。尝试确定先前描述的原型抑制剂1-(4-羟基苄基)咪唑-2-硫酮中硫酮硫原子的取代基团。对软硫酮基团的氧和氮类似物进行合成和评估，结果表明硫原子对于最佳活性是必需的。另外制备了一系列咪唑-2-硫酮类似物，以探究配体基团的pKa与抑制效力之间的关系。结果表明，在大约10个pKa单位的范围内，体外抑制效力与配体pKa不相关，并对此提出了一种解释。为了探索酶氧结合位点的体积耐受性，并确定用六元配体基团取代五元咪唑-2-硫酮配体的效果，还进行了其他配体修饰。
