An orally active corticotropin releasing factor 1 receptor antagonist from 8-aryl-1,3a,7,8-tetraaza-cyclopenta[a]indenes.
8-Aryl-1,3a,7,8-tetraaza-cyclopenta[a]indenes represent a novel series of high-affinity corticotropin-releasing factor-1 receptor (CRF1R) antagonists. Herein we report the synthesis and SAR around the tricyclic core and the anxiolytic activity of an orally dosed exemplary compound 9d (K(i)=8.0 nM) in a mouse canopy model.
Han
Xiaojun
X
Pharmaceutical Research Institute, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA. xiaojun.han@bms.com
Civiello
Rita
R
Pin
Sokhom S
SS
Burris
Kevin
K
Balanda
Lynn A
LA
Knipe
Jay
J
Ren
Shelly
S
Fiedler
Tracey
T
Browman
Kaitlin E
KE
Macci
Robert
R
Taber
Matthew T
MT
Zhang
Jie
J
Dubowchik
Gene M
GM
D000284:Administration, Oral; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001372:Aza Compounds / Q000737:chemistry; D003863:Depression / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D007192:Indenes / Q000737:chemistry; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D012995:Solubility; D013329:Structure-Activity Relationship; D013997:Time Factors; D014867:Water / Q000737:chemistry
D000928:Antidepressive Agents; D001372:Aza Compounds; D007192:Indenes; D018019:Receptors, Corticotropin-Releasing Hormone; D014867:Water