Design and synthesis of tricyclic imidazo[4,5-b]pyridin-2-ones as corticotropin-releasing factor-1 antagonists.
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.
Guo
Zhiqiang
Z
Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA. zguo@neurocrine.com
Tellew
John E
JE
Gross
Raymond S
RS
Dyck
Brian
B
Grey
Jonathan
J
Haddach
Mustapha
M
Kiankarimi
Mehrak
M
Lanier
Marion
M
Li
Bin-Feng
BF
Luo
Zhiyong
Z
McCarthy
James R
JR
Moorjani
Manisha
M
Saunders
John
J
Sullivan
Robert
R
Zhang
Xiaohu
X
Zamani-Kord
Said
S
Grigoriadis
Dimitri E
DE
Crowe
Paul D
PD
Chen
Ta Kung
TK
Williams
John P
JP
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
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