Optimization of Novel Antagonists to the Neurokinin‑3 Receptor for the Treatment of Sex-Hormone Disorders (Part II)

Optimization of Novel Antagonists to the Neurokinin‑3 Receptor for the Treatment of Sex-Hormone Disorders (Part II)

Further lead optimization on N-acyl-triazolopiperazine antagonists to the neurokinin-3 receptor (NK3R) based on the concurrent improvement in bioactivity and ligand lipophilic efficiency (LLE) is reported. Overall, compound 3 (LLE > 6) emerged as the most efficacious in castrated rat and monkey t...

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Veröffentlicht in:ACS medicinal chemistry letters 2015-07, Vol.6 (7), p.736-740
Hauptverfasser: Hoveyda, Hamid R, Fraser, Graeme L, Dutheuil, Guillaume, El Bousmaqui, Mohamed, Korac, Julien, Lenoir, François, Lapin, Alexey, Noël, Sophie
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Sprache:eng
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Zusammenfassung:Further lead optimization on N-acyl-triazolopiperazine antagonists to the neurokinin-3 receptor (NK3R) based on the concurrent improvement in bioactivity and ligand lipophilic efficiency (LLE) is reported. Overall, compound 3 (LLE > 6) emerged as the most efficacious in castrated rat and monkey to lower plasma LH, and it displayed the best off-target safety profile that led to its clinical candidate nomination for the treatment of sex-hormone disorders.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.5b00117