title: Design and synthesis of tricyclic corticotropin-releasing factor-1 antagonists.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, 12790 El Camino Real, San Diego, California 92130, USA.
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Gross
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Guo
authors.forename: Brian
authors.initials: B
authors.lastname: Dyck
authors.forename: Tim
authors.initials: T
authors.lastname: Coon
authors.forename: Charles Q
authors.initials: CQ
authors.lastname: Huang
authors.forename: Richard F
authors.initials: RF
authors.lastname: Lowe
authors.forename: Dragan
authors.initials: D
authors.lastname: Marinkovic
authors.forename: Manisha
authors.initials: M
authors.lastname: Moorjani
authors.forename: Jodene
authors.initials: J
authors.lastname: Nelson
authors.forename: Said
authors.initials: S
authors.lastname: Zamani-Kord
authors.forename: Dimitri E
authors.initials: DE
authors.lastname: Grigoriadis
authors.forename: Sam R J
authors.initials: SR
authors.lastname: Hoare
authors.forename: Paul D
authors.initials: PD
authors.lastname: Crowe
authors.forename: Jane Han
authors.initials: JH
authors.lastname: Bu
authors.forename: Mustapha
authors.initials: M
authors.lastname: Haddach
authors.forename: James
authors.initials: J
authors.lastname: McCarthy
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Robert
authors.initials: R
authors.lastname: Sullivan
authors.forename: Takung
authors.initials: T
authors.lastname: Chen
authors.forename: John P
authors.initials: JP
authors.lastname: Williams
mesh_terms: 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
chemical_list: 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