Wu N C, Chiang C H, Lee A R
Air Force General Hospital, Taipei, Taiwan, Republic of China.
J Ocul Pharmacol. 1993 Summer;9(2):97-108. doi: 10.1089/jop.1993.9.97.
A series of thiadiazole derivatives of carbonic anhydrase inhibitors were prepared and their physicochemical properties and pharmacological activities such as corneal permeabilities, inhibition of carbonic anhydrase activities were evaluated. The solubilities and pKa values were determined in varied pH of phosphate buffers at 35 degrees C after equilibrium. Intrinsic solubility and pKa value were calculated from the plot of solubility versus the reciprocal of hydrogen ion concentration. The distribution coefficient was determined in the system of octanol/pH 7.65 phosphate buffer. As a result, the sigma (Hammett constant) and pi (hydrophobic substituent constant) values of substituents were found to be correlated to the logarithm of Ka and partition coefficient. Corneal permeabilities of the analogue were determined in a specially designed diffusion cell using excised rabbit cornea, which ranged from 1.32 x 10(-5) (compound II) to 3.48 x 10(-7) cm/sec (compound VI). Compound with high permeability might be expected to be absorbed well after topical administration into the eye. The methodology of pH-stat was used to determine the inhibition of the carbonic anhydrase activity of the analogue. The IC50 values of the analogue around 10(-8) M as determined were less than that of acetazolamide. The results suggest that the analogue had good pharmacological activity. Finally, an equation for quantitative structure-activity relationship was established for the analogue, which is as follows: [formula: see text]
制备了一系列碳酸酐酶抑制剂的噻二唑衍生物，并对其理化性质和药理活性进行了评估，如角膜渗透率、碳酸酐酶活性抑制等。在35℃下达到平衡后，在不同pH值的磷酸盐缓冲液中测定溶解度和pKa值。根据溶解度与氢离子浓度倒数的关系图计算固有溶解度和pKa值。在正辛醇/pH 7.65磷酸盐缓冲液体系中测定分配系数。结果发现，取代基的σ（哈米特常数）和π（疏水取代基常数）值与Ka的对数和分配系数相关。使用切除的兔角膜在专门设计的扩散池中测定类似物的角膜渗透率，范围为1.32×10^(-5)（化合物II）至3.48×10^(-7) cm/秒（化合物VI）。具有高渗透率的化合物预期在局部给药到眼内后能被良好吸收。采用pH计法测定类似物对碳酸酐酶活性的抑制作用。所测定的类似物的IC50值约为10^(-8) M，低于乙酰唑胺的IC50值。结果表明该类似物具有良好的药理活性。最后，为该类似物建立了定量构效关系方程，如下所示：[公式：见原文]
