The discovery of VU0486846: steep SAR from a series of M PAMs based on a novel benzomorpholine core.

Bertron JL, Cho HP, Garcia-Barrantes PM, Panarese JD, Salovich JM, Nance KD, Engers DW, Rook JM, Blobaum AL, Niswender CM, Stauffer SR, Conn PJ, Lindsley CW
Bioorg Med Chem Lett. 2018 28 (12): 2175-2179

PMID: 29754948 · PMCID: PMC6427922 · DOI:10.1016/j.bmcl.2018.05.009

This letter describes the chemical optimization of a new series of M positive allosteric modulators (PAMs) based on a novel benzomorpholine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0486846 (7), devoid of adverse effect liability. This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0486846 and details all of the challenges faced in allosteric modulator programs (both steep and flat SAR, as well as subtle structural changes affecting CNS penetration and overall physiochemical and DMPK properties).

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MeSH Terms (11)

Animals CHO Cells Cricetulus Drug Discovery Humans Molecular Structure Morpholines Pyrazoles Rats Receptor, Muscarinic M1 Structure-Activity Relationship

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