解决喹啉系列口服 PDE4 抑制剂中的种属特异性代谢和溶解度问题。
Addressing species specific metabolism and solubility issues in a quinoline series of oral PDE4 inhibitors.
机构信息
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, England, UK.
出版信息
Bioorg Med Chem Lett. 2010 Jan 1;20(1):137-40. doi: 10.1016/j.bmcl.2009.11.010. Epub 2009 Nov 10.
PMID:19932963
Abstract
Species specific conversion of the lead PDE4 inhibitor 1 to the quinolone 3 was identified as the major route of metabolism in the cynomolgus monkey. Modification of the template to give the cinnoline 9 retained potency and selectivity, and greatly improved the pharmacokinetic profile in the cynomolgus monkey compared with 1. Additional SAR studies aimed at improving the solubility of 9 are also described.
摘要
在食蟹猴中，先导 PDE4 抑制剂 1 向喹诺酮 3 的种属特异性转化被确定为主要代谢途径。对模板进行修饰得到的苯并[c]哒嗪 9 保留了活性和选择性，与 1 相比，大大改善了在食蟹猴中的药代动力学特征。还描述了旨在提高 9 的溶解度的其他 SAR 研究。
Zotero 插件