1. 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.
- Author
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Poslusney, Michael S., Salovich, James M., Wood, Michael R., Melancon, Bruce J., Bollinger, Katrina A., Luscombe, Vincent B., Rodriguez, Alice L., Engers, Darren W., Bridges, Thomas M., Niswender, Colleen M., Jeffrey Conn, P., and Lindsley, Craig W.
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ALLOSTERIC regulation , *INTRAMOLECULAR catalysis , *HYDROGEN bonding , *CARBOXAMIDES , *PYRAZOLES - Abstract
Graphical abstract Highlights • First description of the role of the β-aminocarboxamide moiety within M 4 PAM scaffolds. • Novel des -amino and tricyclic variant M 4 PAMs. • The role of the IMHB motif was established, and could be re-enforced by tricycles. 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 4 PAMs and question if the NH 2 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 2 , generating des -amino congeners and surveyed other functional groups in the β-position. These modifications led to weak M 4 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 4 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 4 PAM activity within classical bicyclic M 4 PAM scaffolds. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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