Pfizer Global Research & Development, Eastern Point Road, Groton CT 06340, United States.
Bioorg Med Chem Lett. 2010 Feb 1;20(3):907-11. doi: 10.1016/j.bmcl.2009.12.071. Epub 2009 Dec 23.
We describe a novel series of inhibitors of the type 1 glycine transporter (GlyT1) as an approach to relieving the glutamatergic deficit that is thought to underlie schizophrenia. Synthesis and SAR follow-up of a series of octahydro-cyclopenta[c]pyrrole derivatives afforded potent in vitro inhibition of GlyT1 as well as in vivo activity in elevating CSF glycine. We also found that a 3-O(c-pentyl), 4-F substituent may serve as a surrogate for the widely used 3-trifluoromethoxy group, suggesting its application as an isostere for future medicinal chemistry studies.
我们描述了一系列新型的 1 型甘氨酸转运体（GlyT1）抑制剂，作为一种缓解谷氨酸能不足的方法，而谷氨酸能不足被认为是精神分裂症的基础。一系列八氢环戊[c]吡咯衍生物的合成和 SAR 后续研究提供了对 GlyT1 的有效体外抑制以及体内升高 CSF 甘氨酸的活性。我们还发现 3-O(c-戊基），4-F 取代基可以替代广泛使用的 3-三氟甲氧基基团，这表明它可以作为未来药物化学研究的同系物。
