Discovery of a Novel sp3‑Rich M1 Positive Allosteric Modulators (PAMs) Chemotype via Scaffold Hopping.

Abstract

The M₁ 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 M₁ 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 sp³ carbon atoms and increase Fsp³ values; the fraction of sp³ hybridized carbons. Determining the correct location to incorporate sp³ 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 sp³-rich M₁ positive allosteric modulator series utilizing a N-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 sp³-rich N-cyclopentyl pyrazole-based M₁ PAM scaffold offers a promising structure-activity relationship starting point to discover structurally distinct M₁ PAM chemotypes.