Development of the First Potent, Selective and CNS penetrant M5 Negative Allosteric Modulator (NAM)

Excerpt

A recently completed functional, high throughput screen of the Molecular Libraries Probe Production Center's Network (MLPCN) screening deck of ∼360,000 compounds conducted by Scripps Research Institute Molecular Screening Center (SRIMSC) against three of the five muscarinic receptor subtypes (M₁, M₄ and M₅) provided a number of interesting hits. As this was the first time a directed effort had been undertaken to identify M₅ selective leads, we were very pleased by the identification of nine M₅ PAMs and nine M₅ antagonists (or negative allosteric modulators, NAMs), despite the complete absence of M₅ agonist hits. The most promising M₅ inhibitor hit (CID 5189681), was quickly developed into a potent, selective and CNS penetrant probe molecule ML375 (hM₅ NAM IC₅₀ = 300 nM, hM_1-4 IC₅₀s >30 μM) displaying enantioselective inhibition. Detailed molecular pharmacology studies demonstrated that ML375 is the first M₅ NAM ever described, and ML375 show good rat and cyno pharmacokinetics to support in vivo studies in rodents and non-human primates.