Optimization of 5-phenyl-3-pyridinecarbonitriles as PKCtheta inhibitors.
The key intermediate, 4-chloro-5-iodo-3-pyridinecarbonitrile, allowed for ready optimization of the PKCtheta inhibitory activity of a series of 3-pyridinecarbonitriles. Analog 13b with a 4-methylindol-5-ylamino group at C-4 and a 4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl group at C-5 had an IC(50) value of 7.4nM for the inhibition of PKCtheta.
Boschelli
Diane H
DH
Wyeth Research, Chemical Sciences, 401 N. Middletown Road, Pearl River, NY 10965, United States. bosched@wyeth.com
Wang
Daniel
D
Prashad
Amar S
AS
Subrath
Joan
J
Wu
Biqi
B
Niu
Chuan
C
Lee
Julie
J
Yang
Xiaoke
X
Brennan
Agnes
A
Chaudhary
Divya
D
D000818:Animals; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000074121:Protein Kinase C-theta; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
C542900:5-phenyl-3-pyridinecarbonitrile-(4-methylindol-5-ylamino)-5-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl; D007211:Indoles; D007527:Isoenzymes; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C509176:pyridine-3-carbonitrile; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta