Synthesis and evaluation of carbamate and aryl ether substituted pyrazinones as corticotropin releasing factor-1 (CRF1) receptor antagonists

[Display omitted] A series of pyrazinone-based compounds incorporating either carbamate or aryl ether groups was synthesized and evaluated as corticotropin-releasing factor-1 (CRF1) receptor antagonists. Structure–activity relationship studies led to the identification of highly potent CRF1 receptor...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2016-05, Vol.26 (9), p.2184-2187
Hauptverfasser:	Ahuja, Vijay T., Hartz, Richard A., Molski, Thaddeus F., Mattson, Gail K., Lentz, Kimberley A., Grace, James E., Lodge, Nicholas J., Bronson, Joanne J., Macor, John E.
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Carbamates - chemical synthesis Carbamates - metabolism Carbamates - pharmacology Cell Line, Tumor CRF CRF1 receptor antagonists Depression Humans Microsomes, Liver - metabolism Neuroscience Pyrazines - chemical synthesis Pyrazines - metabolism Pyrazines - pharmacology Pyrazinones Rats Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors Structure-Activity Relationship
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Zusammenfassung:	[Display omitted] A series of pyrazinone-based compounds incorporating either carbamate or aryl ether groups was synthesized and evaluated as corticotropin-releasing factor-1 (CRF1) receptor antagonists. Structure–activity relationship studies led to the identification of highly potent CRF1 receptor antagonists 14a (IC50=0.74nM) and 14b (IC50=1.9nM). The synthesis, structure–activity relationships and in vitro metabolic stability properties of compounds in this series will be described.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2016.03.067