可穿透血脑屏障的可溶性吡唑酰胺类EP1受体拮抗剂的发现。
Discovery of brain penetrant, soluble, pyrazole amide EP1 receptor antagonists.
作者信息
Hall Adrian, Billinton Andy, Bristow Alan K, Brown Susan H, Chowdhury Anita, Cutler Leanne, Giblin Gerard M P, Goldsmith Paul, Hayhow Thomas G, Kilford Ian R, Naylor Alan, Passingham Barry, Rawlings D Anthony
机构信息
Neurolosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.
出版信息
Bioorg Med Chem Lett. 2008 Jul 15;18(14):4027-32. doi: 10.1016/j.bmcl.2008.05.118. Epub 2008 Jun 5.
We describe the discovery of a series of pyrazole amide EP(1) receptor antagonists with good aqueous solubility and CNS penetration. In order to achieve solubility we investigated the incorporation of a basic group in the region of the molecule previously occupied by a carboxylic acid, which was known to be a key element of the pharmacophore. This study led to the identification of compounds such as 4h, 4j and 10b which demonstrated brain-to-blood ratios of 0.8:1-2.0:1 in addition to good solubility and metabolic stability.
我们描述了一系列具有良好水溶性和中枢神经系统渗透性的吡唑酰胺EP(1)受体拮抗剂的发现。为了实现溶解性，我们研究了在分子中先前被羧酸占据的区域引入一个碱性基团，已知羧酸是药效团的关键元素。这项研究导致了化合物4h、4j和10b的鉴定，这些化合物除了具有良好的溶解性和代谢稳定性外，脑血比还为0.8:1 - 2.0:1。
Zotero 插件