Design and synthesis of tricyclic corticotropin-releasing factor-1 antagonists.
Antagonists of the corticotropin-releasing factor (CRF) neuropeptide should prove to be effective in treating stress and anxiety-related disorders. In an effort to identify antagonists with improved physicochemical properties, new tricyclic CRF(1) antagonists were designed, synthesized, and tested for biological activity. As a result of studies aimed at establishing a relationship between structure and CRF(1) binding affinity, NBI 35965 (12a) was identified as a high-affinity antagonist with a pK(i) value of 8.5. Compound 12a proved to be a functional CRF(1) antagonist with pIC(50) values of 7.1 and 6.9 in the in vitro CRF-stimulated cAMP accumulation and ACTH production assays, respectively, and 12a also reduced CRF or stress induced ACTH production in vivo.
Gross
Raymond S
RS
Department of Medicinal Chemistry, Neurocrine Biosciences, 12790 El Camino Real, San Diego, California 92130, USA.
Guo
Zhiqiang
Z
Dyck
Brian
B
Coon
Tim
T
Huang
Charles Q
CQ
Lowe
Richard F
RF
Marinkovic
Dragan
D
Moorjani
Manisha
M
Nelson
Jodene
J
Zamani-Kord
Said
S
Grigoriadis
Dimitri E
DE
Hoare
Sam R J
SR
Crowe
Paul D
PD
Bu
Jane Han
JH
Haddach
Mustapha
M
McCarthy
James
J
Saunders
John
J
Sullivan
Robert
R
Chen
Takung
T
Williams
John P
JP
D000073:Acenaphthenes; D000324:Adrenocorticotropic Hormone / Q000096:biosynthesis; D000818:Animals; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis; D015195:Drug Design; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008968:Molecular Conformation; D010903:Pituitary Gland, Anterior / Q000166:cytology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000099052:CRF Receptor, Type 1
C504986:6-cyclopropylmethyl-2-(2,4-dichlorophenyl)-7-ethyl-4-methyl-7,8-dihydro-6H-1,3,6,8a-tetraazaacenaphthylene; D000073:Acenaphthenes; D006575:Heterocyclic Compounds, 3-Ring; D011720:Pyrazoles; D011725:Pyridines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP