Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA.
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Bioorg Med Chem Lett. 2019 Feb 1;29(3):362-366. doi: 10.1016/j.bmcl.2018.12.039. Epub 2018 Dec 18.
This letter describes a focused exercise to explore the role of the β-amino carboxamide moiety found in all of the first generation M PAMs and question if the NH group served solely to stabilize an intramolecular hydrogen bond (IMHB) and enforce planarity. To address this issue (and to potentially find a substitute for the β-amino carboxamide that engendered P-gp and contributed to solubility liabilities), we removed the NH, generating des-amino congeners and surveyed other functional groups in the β-position. These modifications led to weak M PAMs with poor DMPK properties. Cyclization of the β-amino carboxamide moiety by virtue of a pyrazole ring re-enforced the IMHB, led to potent (and patented) M PAMs, many as potent as the classical bicyclic β-amino carboxamide analogs, but with significant CYP1A2 inhibition. Overall, this exercise indicated that the β-amino carboxamide moiety most likely facilitates an IMHB, and is essential for M PAM activity within classical bicyclic M PAM scaffolds.
这封信描述了一项集中探讨的工作，旨在探索第一代 M PAMs 中所有存在的β-氨基甲酰胺部分的作用，并质疑 NH 基团是否仅用于稳定分子内氢键（IMHB）并强制平面性。为了解决这个问题（并可能找到取代β-氨基甲酰胺的方法，该取代物会引起 P-糖蛋白并导致溶解度问题），我们去除了 NH，生成了去氨基同系物，并在β-位上调查了其他官能团。这些修饰导致了弱的 M PAMs，具有较差的 DMPK 性质。通过吡唑环使β-氨基甲酰胺部分环化，重新增强了 IMHB，导致了有效的（并已获得专利）M PAMs，许多与经典的双环β-氨基甲酰胺类似物一样有效，但对 CYP1A2 有明显抑制作用。总体而言，这项工作表明β-氨基甲酰胺部分很可能有助于形成 IMHB，并且对于经典双环 M PAM 支架内的 M PAM 活性是必不可少的。
