Novel M4 positive allosteric modulators derived from questioning the role and impact of a presumed intramolecular hydrogen-bonding motif in β-amino carboxamide-harboring ligands.
Novel M4 positive allosteric modulators derived from questioning the role and impact of a presumed intramolecular hydrogen-bonding motif in β-amino carboxamide-harboring ligands.
复制标题
新型 M4 正变构调节剂源自质疑β-氨基甲酰胺基配体中假定的分子内氢键基序的作用和影响。
DOI：
10.1016/j.bmcl.2018.12.039
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发表时间：
2019
影响因子：
2.7
通讯作者：
Lindsley,CraigW
中科院分区：
文献类型：
--
作者：
Poslusney,MichaelS;Salovich,JamesM;Wood,MichaelR;Melancon,BruceJ;Bollinger,KatrinaA;Luscombe,VincentB;Rodriguez,AliceL;Engers,DarrenW;Bridges,ThomasM;Niswender,ColleenM;Conn,PJeffrey;Lindsley,CraigW
This letter describes a focused exercise to explore the role of the β-amino carboxamide moiety found in all of the first generation M4PAMs and question if the NH2group 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 NH2, generatingdes-amino congeners and surveyed other functional groups in the β-position. These modifications led to weak M4PAMs 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) M4PAMs, 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 M4PAM activity within classical bicyclic M4PAM scaffolds.
