Titz Alexander, Patton John, Alker André M, Porro Michele, Schwardt Oliver, Hennig Michael, Francotte Eric, Magnani John, Ernst Beat
Institute of Molecular Pharmacy, University of Basel, CH-4056 Basel, Switzerland.
Bioorg Med Chem. 2008 Jan 15;16(2):1046-56. doi: 10.1016/j.bmc.2007.07.025. Epub 2007 Aug 22.
The selectins play a key role in the inflammatory process, that is, the recruitment of leukocytes from blood vessels into inflamed tissue. Because excessive infiltration of leukocytes can induce acute or chronic reactions, the control of leukocyte extravasation is of great pharmaceutical interest. All physiological ligands of the selectins contain the tetrasaccharide epitope sialyl Lewis(x), which therefore became the lead structure in selectin antagonist research. Previous studies indicated that an important factor for the affinity of sLe(x) is the fact that in solution its pharmacophores are already conformationally pre-organized in the bioactive orientation. In mimics where the GlcNAc- and the NeuNAc-moieties of sLe(x) were replaced by (R,R)-cyclohexane-1,2-diol and (S)-cyclohexyllactic acid, respectively, an optimized pre-organization of the pharmacophores could be realized, leading to antagonists with improved affinities. To further optimize the pre-organization of the carboxylic acid, a pharmacophore essential for binding, the replacement of NeuNAc by bulky (R)- and (S)-adamantyl-lactic acid was studied. Although antagonist (S)-7 showed a slightly reduced affinity, the expected beneficial effect of the (S)-configuration at C-2 of the lactate could be confirmed.
选择素在炎症过程中起关键作用，即白细胞从血管募集到炎症组织中。由于白细胞的过度浸润可引发急性或慢性反应，因此控制白细胞外渗具有重大的药学意义。选择素的所有生理配体均含有四糖表位唾液酸路易斯x，因此它成为选择素拮抗剂研究中的先导结构。先前的研究表明，sLe(x)亲和力的一个重要因素是，在溶液中其药效基团已在生物活性取向上构象预组织。在模拟物中，sLe(x)的GlcNAc和NeuNAc部分分别被(R,R)-环己烷-1,2-二醇和(S)-环己基乳酸取代，可实现药效基团的优化预组织，从而得到亲和力提高的拮抗剂。为了进一步优化对结合至关重要的羧酸的预组织，研究了用庞大的(R)-和(S)-金刚烷基乳酸取代NeuNAc的情况。尽管拮抗剂(S)-7的亲和力略有降低，但可以证实乳酸C-2位的(S)-构型具有预期的有益效果。
