Discovery and optimization of a novel, selective and brain penetrant M1 positive allosteric modulator (PAM): the development of ML169, an MLPCN probe

This Letter describes a chemical lead optimization campaign directed at VU0108370, a weak M₁ PAM hit with a novel chemical scaffold from a functional HTS screen within the MLPCN. An iterative parallel synthesis approach rapidly established SAR for this series and afforded VU0405652 (ML169), a potent, selective and brain penetrant M₁ PAM with an in vitro profile comparable to the prototypical M₁ PAM, BQCA, but with an improved brain to plasma ratio.     

Pharmacological property optimization for allosteric ligands: A medicinal chemistry perspective

New strategies to potentially improve drug safety and efficacy emerge with allosteric programs. Biased allosteric modulators can be designed with high subtype selectivity and defined receptor signaling endpoints, however, selecting the most meaningful parameters for optimization can be perplexing. Historically, “potency hunting” at the expense of physicochemical and pharmacokinetic optimization has led to numerous tool compounds with excellent pharmacological properties but no path to drug development. Conversely, extensive physicochemical and pharmacokinetic screening with only post hoc bias and allosteric characterization has led to inefficacious compounds or compounds with on-target toxicities. This field is rapidly evolving with new mechanistic understanding, changes in terminology, and novel opportunities. The intent of this digest is to summarize current understanding and debates within the field. We aim to discuss, from a medicinal chemistry perspective, the parameter choices available to drive SAR.