First generation 5-vinyl-3-pyridinecarbonitrile PKCtheta inhibitors

Chuansheng Niu; Diane H Boschelli; L Nathan Tumey; Niala Bhagirath; Joan Subrath; Jaechul Shim; Yan Wang; Biqi Wu; Clark Eid; Julie Lee; Xiaoke Yang; Agnes Brennan; Divya Chaudhary

doi:10.1016/j.bmcl.2009.08.086

First generation 5-vinyl-3-pyridinecarbonitrile PKCtheta inhibitors

Bioorg Med Chem Lett. 2009 Oct 15;19(20):5829-32. doi: 10.1016/j.bmcl.2009.08.086. Epub 2009 Aug 29.

Authors

Chuansheng Niu¹, Diane H Boschelli, L Nathan Tumey, Niala Bhagirath, Joan Subrath, Jaechul Shim, Yan Wang, Biqi Wu, Clark Eid, Julie Lee, Xiaoke Yang, Agnes Brennan, Divya Chaudhary

Affiliation

¹ Wyeth Research, Chemical Sciences, 401 N. Middletown Road, Pearl River, NY 10965, USA. [email protected]

PMID: 19762237
DOI: 10.1016/j.bmcl.2009.08.086

Abstract

A series of 5-vinyl-3-pyridinecarbonitriles were synthesized and evaluated as PKCtheta inhibitors. The systematic optimization of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]-3-pyridinecarbonitrile 3 resulted in the identification of compound 23e as a potent PKCtheta inhibitor with good selectivity over PKCdelta.

MeSH terms

Animals
Humans
Isoenzymes / antagonists & inhibitors*
Isoenzymes / metabolism
Microsomes / metabolism
Nitriles / chemical synthesis
Nitriles / chemistry*
Nitriles / pharmacology
Protein Kinase C / antagonists & inhibitors*
Protein Kinase C / metabolism
Protein Kinase C-delta / antagonists & inhibitors
Protein Kinase C-delta / metabolism
Protein Kinase C-theta
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Pyridines / chemical synthesis
Pyridines / chemistry*
Pyridines / pharmacology
Rats
Structure-Activity Relationship

Substances

Isoenzymes
Nitriles
Protein Kinase Inhibitors
Pyridines
PRKCQ protein, human
Protein Kinase C
Protein Kinase C-delta
Protein Kinase C-theta