Indole RSK inhibitors. Part 2: optimization of cell potency and kinase selectivity

Thomas M Kirrane; Stephen J Boyer; Jennifer Burke; Xin Guo; Roger J Snow; Lida Soleymanzadeh; Alan Swinamer; Yunlong Zhang; Jeffery B Madwed; Mohammed Kashem; Stanley Kugler; Margaret M O'Neill

doi:10.1016/j.bmcl.2011.10.029

Indole RSK inhibitors. Part 2: optimization of cell potency and kinase selectivity

Bioorg Med Chem Lett. 2012 Jan 1;22(1):738-42. doi: 10.1016/j.bmcl.2011.10.029. Epub 2011 Oct 18.

Authors

Thomas M Kirrane¹, Stephen J Boyer, Jennifer Burke, Xin Guo, Roger J Snow, Lida Soleymanzadeh, Alan Swinamer, Yunlong Zhang, Jeffery B Madwed, Mohammed Kashem, Stanley Kugler, Margaret M O'Neill

Affiliation

¹ Department of Medicinal Chemistry, Boehringer-Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA. [email protected]

PMID: 22056746
DOI: 10.1016/j.bmcl.2011.10.029

Abstract

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 optimized for cellular potency and kinase selectivity. This led to the identification of compound 24, BIX 02565, an attractive candidate for use in vitro and in vivo to explore the role of RSK as a target for the treatment heart failure.

MeSH terms

Amides / chemistry
Chemistry, Pharmaceutical / methods
Crystallography, X-Ray / methods
Drug Design
Drug Evaluation, Preclinical / methods
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology*
Humans
Indoles / chemistry*
Inhibitory Concentration 50
Models, Chemical
Molecular Conformation
Nitrogen / chemistry
Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors*
Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
Structure-Activity Relationship

Substances

Amides
Enzyme Inhibitors
Indoles
Ribosomal Protein S6 Kinases, 90-kDa
Nitrogen