The Discovery of the MCH-1 Receptor Antagonist NGD-4715 for the Potential Treatment of Obesity
Comprehensive Medicinal Chemistry III
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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Tarrant, J., Hodgetts, K. J., Chenard, B. L., & Krause, J. E. (2017). The Discovery of the MCH-1 Receptor Antagonist NGD-4715 for the Potential Treatment of Obesity. Comprehensive Medicinal Chemistry III, 8, 488-515. http://dx.doi.org/10.1016/B978-0-12-409547-2.13785-0