Koga H, Sato H, Dan T, Aoki B
Fuji-gotemba Research Laboratories, Chugai Pharmaceutical Company, Ltd., Shizuoka, Japan.
J Med Chem. 1991 Sep;34(9):2702-8. doi: 10.1021/jm00113a006.
Attempts to develop new (aryloxy)acetic acids with a better profile of diuretic and uricosuric activities as well as with fewer side effects have produced a series of compounds in which the ring system has been varied. Diuretic screening of these analogues in rats indicated that the great difference in the activity between these compounds might be ascribed to a difference in the ring system rather than that in the substituent effect and that the annulation hypothesis described before is not necessarily applicable to all of these compounds. This prompted us to study the relationship between the structure and the diuretic activity of the (aryloxy)acetic acids. An active model (receptor model) was created with the indanone moiety of R-(-)-3 and the dihydrobenzofuran-2-carboxylic acid moiety of S-(+)-4. The three-dimensional structure-activity study of known compounds 2-4, and 5a using the active model showed that the degree of fitting to the model is related to the diuretic activity of these compounds. This was also confirmed for compounds 6a, 6b, 9a, 10a, 11a, 12a, 13a, 14a, 15a, and 16a, and the relation between the structure and the diuretic activity was rationalized qualitatively. With these insights in mind, a modified receptor model was constructed. We believe that this model is useful for a prediction of the activity of compounds not yet synthesized as well as for designing new (aryloxy)acetic acid diuretics.
开发具有更好利尿和促尿酸排泄活性以及更少副作用的新型（芳氧基）乙酸的尝试产生了一系列环系有所变化的化合物。在大鼠中对这些类似物进行利尿筛选表明，这些化合物之间活性的巨大差异可能归因于环系的差异，而非取代基效应的差异，并且之前描述的环合假说不一定适用于所有这些化合物。这促使我们研究（芳氧基）乙酸的结构与利尿活性之间的关系。利用R-(-)-3的茚满酮部分和S-(+)-4的二氢苯并呋喃-2-羧酸部分创建了一个活性模型（受体模型）。使用该活性模型对已知化合物2 - 4和5a进行的三维构效关系研究表明，与模型的契合程度与这些化合物的利尿活性相关。对于化合物6a、6b、9a、10a、11a、12a、13a、14a、15a和16a也证实了这一点，并且结构与利尿活性之间的关系在定性上得到了合理说明。基于这些认识，构建了一个改进的受体模型。我们相信该模型对于预测尚未合成的化合物的活性以及设计新型（芳氧基）乙酸利尿剂是有用的。
