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Novel M 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 Michael S , Salovich JM James M , Wood MR Michael R , Melancon BJ Bruce J , Bollinger KA Katrina A , Luscombe VB Vincent B , Rodriguez AL Alice L , Engers DW Darren W , Bridges TM Thomas M , Niswender CM Colleen M , Conn PJ P Jeffrey , Lindsley CW Craig W .
Bioorganic & medicinal chemistry letters. 2018 12 18; 29(3).
362-366

Abstract

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.

Tags: 2018