Novel M<sub>4</sub> positive allosteric modulators derived from questioning the role and impact of a presumed intramolecular hydrogen-bonding motif in...

Basic Information

ID: ALA4371085

Journal: Bioorg Med Chem Lett

Title: 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.

Authors: Poslusney MS, Salovich JM, Wood MR, Melancon BJ, Bollinger KA, Luscombe VB, Rodriguez AL, Engers DW, Bridges TM, Niswender CM, Conn PJ, Lindsley CW.

Abstract: This letter describes a focused exercise to explore the role of the β-amino carboxamide moiety found in all of the first generation M₄ PAMs and question if the NH₂ 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 NH₂, generating des-amino congeners and surveyed other functional groups in the β-position. These modifications led to weak M₄ 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) M₄ 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 M₄ PAM activity within classical bicyclic M₄ PAM scaffolds.

CiteXplore: 30580918

DOI: 10.1016/j.bmcl.2018.12.039

Patent ID: ┄

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