High-throughput screening campaigns have identified novel chemical matter for many medicinal chemistry programs, and progression of these hits is predicated on reliable and scalable synthetic strategies. The synthesis and SAR exploration of multiple HTS hits from two distinct neuroscience programs is discussed. 4,4-Disubstituted quinazolinone 1 was identified as a T-type calcium channel antagonist for the potential treatment of CNS disorders. A focused SAR campaign driven by the optimization of potency, metabolic stability, and pharmacokinetic profile identified potent T-type Ca2+ channel antagonists for in vivo evaluation. Cyclohexylureas 2 and 3 were identified as novel alanine-serine-cysteine transporter-1 (ASC-1) inhibitors for the potential treatment of schizophrenia and Alzheimer’s disease. The challenging optimization of the synthesis of 2 for hit confirmation and the SAR of 3, optimized for potency and Pgp susceptibility, will be highlighted.

Synthetic chemistry enabling hit-to-lead progression of T-type Ca2+ channel antagonists and ASC-1 inhibitors

2019 Fall National Meeting

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