Discovery and SAR of a novel series of potent, CNS penetrant M4 PAMs based on a non-enolizable ketone core: Challenges in disposition.
Basic Information
ID: ALA4477243
Journal: Bioorg Med Chem Lett
Title: Discovery and SAR of a novel series of potent, CNS penetrant M4 PAMs based on a non-enolizable ketone core: Challenges in disposition.
Authors: Wood MR, Noetzel MJ, Tarr JC, Rodriguez AL, Lamsal A, Chang S, Foster JJ, Smith E, Chase P, Hodder PS, Engers DW, Niswender CM, Brandon NJ, Wood MW, Duggan ME, Conn PJ, Bridges TM, Lindsley CW.
Abstract: This Letter describes the chemical optimization of a novel series of M4 PAMs based on a non-enolizable ketone core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent, selective and CNS penetrant; however, the compound was highly cleared in vitro and in vivo. SAR provided analogs for which M4 PAM potency and CNS exposure were maintained; yet, clearance remained high. Metabolite identification studies demonstrated that this series was subject to rapid, and near quantitative, reductive metabolism to the corresponding secondary alcohol metabolite that was devoid of M4 PAM activity.
CiteXplore: 27476142
DOI: 10.1016/j.bmcl.2016.07.042
Patent ID: ┄