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

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

Author information

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

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.

PMID:
19632115
DOI:
10.1016/j.bmcl.2009.07.022
[Indexed for MEDLINE]

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