An orally active corticotropin releasing factor 1 receptor antagonist from 8-aryl-1,3a,7,8-tetraaza-cyclopenta[a]indenes

Xiaojun Han; Rita Civiello; Sokhom S Pin; Kevin Burris; Lynn A Balanda; Jay Knipe; Shelly Ren; Tracey Fiedler; Kaitlin E Browman; Robert Macci; Matthew T Taber; Jie Zhang; Gene M Dubowchik

doi:10.1016/j.bmcl.2007.01.008

An orally active corticotropin releasing factor 1 receptor antagonist from 8-aryl-1,3a,7,8-tetraaza-cyclopenta[a]indenes

Bioorg Med Chem Lett. 2007 Apr 1;17(7):2026-30. doi: 10.1016/j.bmcl.2007.01.008. Epub 2007 Jan 13.

Authors

Xiaojun Han¹, Rita Civiello, Sokhom S Pin, Kevin Burris, Lynn A Balanda, Jay Knipe, Shelly Ren, Tracey Fiedler, Kaitlin E Browman, Robert Macci, Matthew T Taber, Jie Zhang, Gene M Dubowchik

Affiliation

¹ Pharmaceutical Research Institute, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA. xiaojun.han@bms.com

PMID: 17258456
DOI: 10.1016/j.bmcl.2007.01.008

Abstract

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.

MeSH terms

Administration, Oral
Animals
Antidepressive Agents / pharmacology
Aza Compounds / chemistry
Depression / drug therapy
Dose-Response Relationship, Drug
Indenes / chemistry
Kinetics
Mice
Mice, Inbred BALB C
Models, Chemical
Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
Solubility
Structure-Activity Relationship
Time Factors
Water / chemistry

Substances

Antidepressive Agents
Aza Compounds
Indenes
Receptors, Corticotropin-Releasing Hormone
Water