Hajduk Philip J, Shuker Suzanne B, Nettesheim David G, Craig Richard, Augeri David J, Betebenner David, Albert Daniel H, Guo Yan, Meadows Robert P, Xu Lianhong, Michaelides Michael, Davidsen Steven K, Fesik Stephen W
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
J Med Chem. 2002 Dec 19;45(26):5628-39. doi: 10.1021/jm020160g.
The NMR-based discovery of biaryl hydroxamate inhibitors of the matrix metalloproteinase stromelysin (MMP-3) has been previously described (Hajduk et al. J. Am. Chem. Soc. 1997, 119, 5818-5827). While potent in vitro, these inhibitors exhibited no in vivo activity due, at least in part, to the poor pharmacokinetic properties of the alkylhydroxamate moiety. To circumvent this liability, NMR-based screening was implemented to identify alternative zinc-chelating groups. Using this technique, 1-naphthyl hydroxamate was found to bind tightly to the protein (K(D) = 50 microM) and was identified as a candidate for incorporation into the lead series. On the basis of NMR-derived structural information, the naphthyl hydroxamate and biaryl fragments were linked together to yield inhibitors of this enzyme that exhibited improved bioavailability. These studies demonstrate that the NMR-based screening of fragments can be effectively applied to improve the physicochemical or pharmacokinetic profile of lead compounds.
基于核磁共振技术发现基质金属蛋白酶基质溶解素（MMP - 3）的联芳基异羟肟酸酯抑制剂的研究此前已有报道（哈杜克等人，《美国化学会志》，1997年，第119卷，5818 - 5827页）。这些抑制剂虽然在体外具有活性，但至少部分由于烷基异羟肟酸酯部分较差的药代动力学性质，在体内没有活性。为了规避这一缺点，实施了基于核磁共振技术的筛选以鉴定替代的锌螯合基团。使用该技术，发现1 - 萘基异羟肟酸酯与蛋白质紧密结合（解离常数K(D) = 50微摩尔），并被鉴定为引入先导系列的候选物。基于核磁共振获得的结构信息，将萘基异羟肟酸酯和联芳基片段连接在一起，得到了该酶的抑制剂，其生物利用度有所提高。这些研究表明，基于核磁共振技术的片段筛选可有效地用于改善先导化合物的物理化学或药代动力学特性。
