MK-8825: A potent and selective CGRP receptor antagonist with good oral activity in rats
MK-8825: A potent and selective CGRP receptor antagonist with good oral activity in rats
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DOI：
10.1016/j.bmcl.2012.04.105
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发表时间：
2012-06-15
影响因子：
2.7
通讯作者：
Salvatore, Christopher A.
中科院分区：
文献类型：
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作者：
Bell, Ian M.;Stump, Craig A.;Salvatore, Christopher A.
对临床应用的降钙素基因相关肽受体拮抗剂MK-3207(3)进行合理的修饰，得到了一种类似物，可增加大鼠血浆中的游离含量，并增强了其在水中的溶解性，即2-[(8R)-8-(3，5-difluorophenyl)-8-methyl-10-oxo-6，9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2‘-oxo-1’，2‘，5，7-tetrahydrospiro[cyclopenta[b]pyridine-6，3’-pyrrolo[2，3-b]吡啶-3-基]乙酰胺(MK-8825)(6)。化合物6在人和大鼠CGRP受体上保持了与3相似的亲和力，但在大鼠药效学模型中具有显著的体内药效。6的总体情况表明，它应该是一种有用的大鼠工具来研究体内CGRP受体阻断的影响。(C)2012爱思唯尔有限公司。保留所有权利。
Rational modification of the clinically tested CGRP receptor antagonist MK-3207 (3) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b] pyridin]-3-yl]acetamide (MK-8825) (6). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP receptor blockade in vivo. (C) 2012 Elsevier Ltd. All rights reserved.