Pierce W M, Sharir M, Waite K J, Chen D, Kaysinger K K
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Kentucky 40292.
Proc Soc Exp Biol Med. 1993 Jul;203(3):360-5. doi: 10.3181/00379727-203-43612.
A novel homologous series of bis(carbonyl)amidothiadiazole sulfonamides has been synthesized for structure-activity relationship studies, and initial characterization has been performed. The goal was synthesis of thiadiazole derivatives with appropriate lipid and water solubilities for utility as topically (corneal application) active carbonic anhydrase (CA) inhibitors. This series has solubility properties and pKa which bracket those of acetazolamide--the prototypical CA inhibitor. All of these compounds are active as in vitro CA inhibitors, and are 10-25% as potent as acetazolamide as in vitro enzyme inhibitors. Two of these compounds act as ocular hypotensive agents after topical application of a single dose to the corneas of normotensive New Zealand albino rabbits. The efficacy of the lead compound of this series (in this one model) is approximately equivalent to that of topical CA inhibitors that are presently in clinical trial. None of these novel compounds reacts to an appreciable extent with free sulfhydryl groups (a predictor of toxicity). This family of compounds will be useful for future studies of ocular pharmacokinetics, as well as ocular and systemic effects of topical administration of CA inhibitors. These and future studies may lead to development of thiadiazole sulfonamides useful in the management of glaucoma.
为了进行构效关系研究，合成了一种新型的双（羰基）氨基噻二唑磺酰胺同系物，并进行了初步表征。目标是合成具有适当脂溶性和水溶性的噻二唑衍生物，用作局部（角膜应用）活性碳酸酐酶（CA）抑制剂。该系列化合物的溶解性和pKa值介于原型CA抑制剂乙酰唑胺的相应值之间。所有这些化合物作为体外CA抑制剂均具有活性，作为体外酶抑制剂，其效力为乙酰唑胺的10%-25%。在对正常血压的新西兰白化兔角膜单次局部给药后，其中两种化合物可作为降眼压剂。该系列先导化合物（在该模型中）的疗效与目前正在进行临床试验的局部CA抑制剂大致相当。这些新型化合物均未与游离巯基发生明显反应（巯基是毒性的预测指标）。该类化合物将有助于未来眼部药代动力学研究，以及CA抑制剂局部给药的眼部和全身效应研究。这些研究以及未来的研究可能会导致开发出可用于青光眼治疗的噻二唑磺酰胺。
