Carbonic Anhydrase-II Inhibition. What are the True Enzyme–Inhibitory Properties of the Sulfamide Cognate of Topiramate?

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• 作者：Bruce E. Maryanoff ; David F. McComsey ; Jung Lee ; Virginia L. Smith-Swintosky ; Yuanping Wang ; Lisa K. Minor ; Matthew J. Todd
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：April 24, 2008
• 年：2008
• 卷：51
• 期：8
• 页码：2518 - 2521
• 全文大小：102K
• 年卷期：v.51,no.8(April 24, 2008)
• ISSN：1520-4804

文摘

The marketed drug topiramate (1) is a moderate inhibitor of carbonic anhydrase-II (CA-II) (K_i or K_d = 0.3–0.6 µM), whereas sulfamide cognate 2 is a comparatively weak inhibitor (K_i or K_d = 25–650 µM). From an X-ray cocrystal structure of 2·CA-II, Winum et al. (J. Med. Chem. 2006, 49, 7024) proposed that an adverse steric interaction between the C8 methyl group in 2 and Ala-65 of CA-II is responsible for the diminished CA-II inhibitory potency of 2. We performed a straightforward test of this Ala-65 effect by synthesizing and examining ligand 3, which lacks the offending (pro-S or C8) methyl substituent in 2. We also prepared and evaluated related sulfamides 5, 7, and 9. In a CA-II inhibition assay (4-nitrophenyl acetate), the K_i for 3 was ~300 µM, indicating very weak inhibition, close to that for 2 (4NPA, K_i = 340 µM). In a CA-II binding assay (ThermoFluor), the K_d for 3 was >57 µM, indicating very weak binding, lower than the affinity of 2 (K_d = 25 µM). Our results draw into question the proposed steric interaction between the C8 methyl of 2 and Ala-65 of CA-II.