A series of inhibitors for the 90 kDa ribosomal S6 kinase (RSK) based on an 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxamide scaffold were identified through high throughput screening.  Utilizing a RSK co-crystal structure, SAR efforts focused on optimization of cellular potency, kinase selectivity and physicochemical properties leading to the discovery of compounds bearing a 3-aminobenzimidazole substituent.  In vivo evaluation of several compounds identified significant blood pressure lowering effects which were discovered to be the result of potent binding to multiple adrenergic receptors.  Transitioning to an aza-indolelactam core and replacement of the aminobenzimidazole group mitigated the undesired adrenergic activity while maintaining good cellular potency and kinase selectivity.

Inhibition of RSK for the treatment of congestive heart failure: Discovery and optimization of a series of indolelactam based inhibitors

244th National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.