8.19 - The Discovery of the MCH-1 Receptor Antagonist NGD-4715 for the Potential Treatment of Obesity

Add time:08/30/2019    Source:sciencedirect.com

For the first time, we disclose the medicinal chemistry efforts at Neurogen Corporation that led to the discovery of the clinical phase I compound NGD-4715 (7), a selective, brain penetrant, orally bioavailable melanin-concentrating hormone receptor 1 antagonist. We discuss the optimization of an arylpiperazine serendipitous hit in a high-throughput screening that led to the discovery of NDT 9522320 (10), a useful tool compound that enabled target validation in rat and dog feeding models. Subsequent medicinal chemistry design led to the bicyclic core of NGD-4715. We recount how we arrived at selecting NGD-4715 as a development candidate and summarize our clinical experience with it. A number of syntheses are presented, which were explored as a prelude to the highly optimized chemical process synthesis used to support the IND-enabling toxicology program and deliver clinical supplies for the phase I studies. We discuss the backup strategy that led to NGD-0589, as well as the discovery of further improved compounds.

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