Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
Bioorg Med Chem Lett. 2012 Jun 15;22(12):3941-5. doi: 10.1016/j.bmcl.2012.04.105. Epub 2012 Apr 30.
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.
经临床测试的降钙素基因相关肽受体拮抗剂 MK-3207（3）的合理修饰提供了一种具有增加的大鼠血浆中游离分数和增强的水溶解度的类似物，2-[(8R)-8-(3,5-二氟苯基）-8-甲基-10-氧代-6,9-二氮杂螺[4.5]癸-9-基]-N-[(6S)-2'-氧代-1',2',5,7-四氢螺[环戊[b]吡啶-6,3'-吡咯[2,3-b]吡啶]-3-基]乙酰胺（MK-8825）（6）。化合物 6 在人源和大鼠 CGRP 受体中保持与 3 相似的亲和力，但在大鼠药效学模型中具有显著改善的体内效力。6 的整体特征表明，它应该可以用作大鼠工具，用于研究体内降钙素基因相关肽受体阻断的作用。
