Substituted benzyloxytricyclic compounds as retinoic acid-related orphan receptor gamma t (RORγt) agonists

[Display omitted] Substituted benzyloxy aryl compound 2 was identified as an RORγt agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as wel...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2020-06, Vol.30 (12), p.127204-127204, Article 127204
Hauptverfasser:	Harikrishnan, Lalgudi S., Gill, Patrice, Kamau, Muthoni G., Qin, Lan-Ying, Ruan, Zheming, O'Malley, Daniel, Huynh, Tram, Stachura, Sylwia, Cavallaro, Cullen L., Lu, Zhonghui, J.-W. Duan, James, Weigelt, Carolyn A., Sack, John S., Ruzanov, Max, Khan, Javed, Gururajan, Murali, Wong, Jessica J., Huang, Yanling, Yarde, Melissa, Li, Zhuyin, Chen, Cliff, Sun, Huadong, Borowski, Virna, Murtaza, Anwar, Fink, Brian E.
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Benzyl Compounds - chemistry Benzyl Compounds - pharmacology Dose-Response Relationship, Drug Female Heterocyclic Compounds - chemistry Heterocyclic Compounds - pharmacology Mice Mice, Inbred C57BL Molecular Structure Receptors, Retinoic Acid - agonists Retinoic Acid Receptor gamma Retinoic acid related orphan receptor ROR gamma RORgt RORγt Structure-Activity Relationship TH17 cells and IL-17
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Zusammenfassung:	[Display omitted] Substituted benzyloxy aryl compound 2 was identified as an RORγt agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2020.127204