Zask A, Jirkovsky I, Nowicki J W, McCaleb M L
Medicinal Chemistry Department, Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000.
J Med Chem. 1990 May;33(5):1418-23. doi: 10.1021/jm00167a022.
A series of 5-(naphthalenylsulfonyl)-2,4-thiazolidinediones were synthesized and evaluated for antihyperglycemic activity in an insulin-resistant, genetically diabetic db/db mouse model of non-insulin-dependent diabetes mellitus (NIDDM). The sulfones could be synthesized by a novel, selective C-5 sulfonylation of dilithio-2,4-thiazolidinedione with appropriate sulfonyl chlorides. Within this series, naphthalene was found to be superior to other groups for eliciting antihyperglycemic activity, including the p-alkoxyphenyl group found in ciglitazone, a prototypical agent for this activity. Attachment of the 5-sulfonyl-2,4-thiazolidinedione moiety to the 2-naphthalene position led to optimum activity. Other linkers between the naphthalene and 2,4-thiazolidinedione rings, such as thio, methylene, oxy, and sulfinyl led to decreased antihyperglycemic activity. The best analogue, 5-(2-naphthalenylsulfonyl)-2,4-thiazolidinedione (AY-31,637) was equipotent to ciglitazone in two animal models of NIDDM.
合成了一系列5-(萘基磺酰基)-2,4-噻唑烷二酮，并在非胰岛素依赖型糖尿病（NIDDM）的胰岛素抵抗、遗传性糖尿病db/db小鼠模型中评估其降血糖活性。这些砜类化合物可通过二锂化-2,4-噻唑烷二酮与适当的磺酰氯进行新型选择性C-5磺酰化反应来合成。在该系列化合物中，发现萘基在引发降血糖活性方面优于其他基团，包括在具有该活性的典型药物环格列酮中发现的对烷氧基苯基。将5-磺酰基-2,4-噻唑烷二酮部分连接到2-萘位可产生最佳活性。萘环与2,4-噻唑烷二酮环之间的其他连接基，如硫代、亚甲基、氧基和亚磺酰基，会导致降血糖活性降低。最佳类似物5-(2-萘基磺酰基)-2,4-噻唑烷二酮（AY-31,637）在两种NIDDM动物模型中的效力与环格列酮相当。
