title: Design and synthesis of tricyclic imidazo[4,5-b]pyridin-2-ones as corticotropin-releasing factor-1 antagonists.
abstract: The synthesis and SAR studies of tricyclic imidazo[4,5-b]pyridin-2-ones as human corticotropin-releasing factor receptor (CRF(1)) antagonists are discussed herein. Compound 16g was identified as a functional antagonist that inhibited CRF-stimulated cyclic adenosine monophosphate production and CRF-induced adrenocorticotrophic hormone release. Pharmacokinetics studies in rats showed that 16g was orally bioavailable, had good brain penetration, and had a moderate half-life. In our effort to identify CRF(1) antagonists with improved pharmacokinetics properties, 16g exhibited a favorably lower volume of distribution.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA. zguo@neurocrine.com
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Guo
authors.forename: John E
authors.initials: JE
authors.lastname: Tellew
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Gross
authors.forename: Brian
authors.initials: B
authors.lastname: Dyck
authors.forename: Jonathan
authors.initials: J
authors.lastname: Grey
authors.forename: Mustapha
authors.initials: M
authors.lastname: Haddach
authors.forename: Mehrak
authors.initials: M
authors.lastname: Kiankarimi
authors.forename: Marion
authors.initials: M
authors.lastname: Lanier
authors.forename: Bin-Feng
authors.initials: BF
authors.lastname: Li
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Luo
authors.forename: James R
authors.initials: JR
authors.lastname: McCarthy
authors.forename: Manisha
authors.initials: M
authors.lastname: Moorjani
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Robert
authors.initials: R
authors.lastname: Sullivan
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Zhang
authors.forename: Said
authors.initials: S
authors.lastname: Zamani-Kord
authors.forename: Dimitri E
authors.initials: DE
authors.lastname: Grigoriadis
authors.forename: Paul D
authors.initials: PD
authors.lastname: Crowe
authors.forename: Ta Kung
authors.initials: TK
authors.lastname: Chen
authors.forename: John P
authors.initials: JP
authors.lastname: Williams
mesh_terms: D000284:Administration, Oral; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D016466:CHO Cells; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015195:Drug Design; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / 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: D006575:Heterocyclic Compounds, 3-Ring; D007093:Imidazoles; D011725:Pyridines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP