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Discovery of a Novel sp‑Rich M Positive Allosteric Modulators (PAMs) Chemotype via Scaffold Hopping

Authors

Bungard JD Joseph D , Spearing P Paul , Nishio Y Yu , Rathnayake U Upendra , Presley CC Chris C , Chang S Sichen , Kling HE Haley E , Thompson AD Analisa D , Cho HP Hyekyung P , Peng L Li , Rodriguez AL Alice L , Niswender CM Colleen M , Boutaud O Olivier , Kramlinger V Valerie , Jones CK Carrie K , Conn PJ P Jeffrey , Engers JL Julie L , Engers DW Darren W , Lindsley CW Craig W , Han C Changho .
ACS medicinal chemistry letters. 2025 06 17; 16(7).
1231-1238

Abstract

The M receptor has long been investigated as a promising CNS drug target, yet further research is essential to fully elucidate compound’s Pharmacodynamic (PD) as well as Toxicokinetic (TK) effects. In this context, the development of structurally diverse and high-profile M PAM tool compounds remains highly valuable, as existing advanced tools exhibit notable structural similarity. One approach that can be considered during scaffold hopping exercise and can improve drug-like properties is to introduce additional sp carbon atoms and increase Fsp values; the fraction of sp hybridized carbons. Determining the correct location to incorporate sp carbon atoms can be challenging, but once the right position is identified, it often leads to novel optimization opportunities. Reported herein is the discovery of a novel sp-rich M positive allosteric modulator series utilizing a -cyclopentyl pyrazole core. Also, an iterative library synthesis approach provided an enhanced understanding of the minimum pharmacophore. Several compounds within the series showed favorable on-target potencies and DMPK properties. In conclusion, the reported sp-rich -cyclopentyl pyrazole-based M PAM scaffold offers a promising structure-activity relationship starting point to discover structurally distinct M PAM chemotypes.