Details

Autor(en) / Beteiligte

• 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
• Conn, P Jeffrey
• Lindsley, Craig W

Titel

Novel M 4 positive allosteric modulators derived from questioning the role and impact of a presumed intramolecular hydrogen-bonding motif in β-amino carboxamide-harboring ligands

Ist Teil von

• Bioorganic & medicinal chemistry letters, 2019-02, Vol.29 (3), p.362

Ort / Verlag

England

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.