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

This letter describes a focused exercise to explore the role of the beta-amino carboxamide moiety found in all of the first generation M-4 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 beta-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 beta-position. These modifications led to weak M-4 PAMs with poor DMPK properties. Cyclization of the beta-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 beta-amino carboxamide analogs, but with significant CYP1A2 inhibition. Overall, this exercise indicated that the beta-amino carboxamide moiety most likely facilitates an IMHB, and is essential for M(4)PAM activity within classical bicyclic M-4 PAM scaffolds.