Maryanoff Bruce E, McComsey David F, Lee Jung, Smith-Swintosky Virginia L, Wang Yuanping, Minor Lisa K, Todd Matthew J
Research & Early Development, Johnson & Johnson Pharmaceutical Research & Development, Spring House, Pennsylvania 19477-0776, USA.
J Med Chem. 2008 Apr 24;51(8):2518-21. doi: 10.1021/jm7015649. Epub 2008 Mar 26.
The marketed drug topiramate ( 1) is a moderate inhibitor of carbonic anhydrase-II (CA-II) ( K i or K d = 0.3-0.6 microM), whereas sulfamide cognate 2 is a comparatively weak inhibitor ( K i or K d = 25-650 microM). 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 approximately 300 microM, indicating very weak inhibition, close to that for 2 (4NPA, K i = 340 microM). In a CA-II binding assay (ThermoFluor), the K d for 3 was >57 microM, indicating very weak binding, lower than the affinity of 2 ( K d = 25 microM). Our results draw into question the proposed steric interaction between the C8 methyl of 2 and Ala-65 of CA-II.
已上市药物托吡酯（1）是碳酸酐酶-II（CA-II）的中度抑制剂（Ki或Kd = 0.3 - 0.6微摩尔），而磺酰胺类似物2是相对较弱的抑制剂（Ki或Kd = 25 - 650微摩尔）。根据2与CA-II的X射线共晶体结构，维努姆等人（《药物化学杂志》，2006年，49卷，7024页）提出，2中C8甲基与CA-II的丙氨酸-65之间存在不利的空间相互作用，这是导致2对CA-II抑制效力降低的原因。我们通过合成并检测配体3对这种丙氨酸-65效应进行了直接测试，配体3在2中缺少引起问题的（前-S或C8）甲基取代基。我们还制备并评估了相关的磺酰胺5、7和9。在CA-II抑制试验（4-硝基苯乙酸）中，3的Ki约为300微摩尔，表明抑制作用非常弱，接近2的抑制作用（4NPA，Ki = 340微摩尔）。在CA-II结合试验（热荧光法）中，3的Kd > 57微摩尔，表明结合作用非常弱，低于2的亲和力（Kd = 25微摩尔）。我们的结果对所提出的2的C8甲基与CA-II的丙氨酸-65之间的空间相互作用提出了质疑。
