4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: potent and selective p70S6 kinase inhibitors

Upul Bandarage; Brian Hare; Jonathan Parsons; Ly Pham; Craig Marhefka; Guy Bemis; Qing Tang; Cameron Stuver Moody; Steve Rodems; Sundeep Shah; Chris Adams; Jose Bravo; Emmanuelle Charonnet; Vladimir Savic; Jon H Come; Jeremy Green

doi:10.1016/j.bmcl.2009.07.022

4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: potent and selective p70S6 kinase inhibitors

Bioorg Med Chem Lett. 2009 Sep 1;19(17):5191-4. doi: 10.1016/j.bmcl.2009.07.022. Epub 2009 Jul 9.

Authors

Upul Bandarage¹, Brian Hare, Jonathan Parsons, Ly Pham, Craig Marhefka, Guy Bemis, Qing Tang, Cameron Stuver Moody, Steve Rodems, Sundeep Shah, Chris Adams, Jose Bravo, Emmanuelle Charonnet, Vladimir Savic, Jon H Come, Jeremy Green

Affiliation

¹ Vertex Pharmaceuticals, Inc., 130 Waverly Street, Cambridge, MA 02139, USA.

PMID: 19632115
DOI: 10.1016/j.bmcl.2009.07.022

Abstract

We report herein the design and synthesis of 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-amine derivatives as inhibitors of p70S6 kinase. Screening hits containing the 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine scaffold were optimized for p70S6K potency and selectivity against related kinases. Structure-based design employing an active site homology model derived from PKA led to the preparation of benzimidazole 5-substituted compounds 26 and 27 as highly potent inhibitors (K(i) <1nM) of p70S6K, with >100-fold selectivity against PKA, ROCK and GSK3.

MeSH terms

Benzimidazoles / chemical synthesis*
Benzimidazoles / chemistry
Benzimidazoles / pharmacology
Binding Sites
Catalytic Domain
Computer Simulation
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / antagonists & inhibitors
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / chemistry
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / metabolism
Drug Design
Glycogen Synthase Kinase 3 / antagonists & inhibitors
Glycogen Synthase Kinase 3 / metabolism
Oxadiazoles / chemical synthesis
Oxadiazoles / chemistry*
Oxadiazoles / pharmacology
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors*
Ribosomal Protein S6 Kinases, 70-kDa / metabolism
Structure-Activity Relationship
rho-Associated Kinases / antagonists & inhibitors
rho-Associated Kinases / metabolism

Substances

Benzimidazoles
Oxadiazoles
Protein Kinase Inhibitors
Ribosomal Protein S6 Kinases, 70-kDa
rho-Associated Kinases
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
Glycogen Synthase Kinase 3