C-5 substituted heteroaryl-3-pyridinecarbonitriles as PKCtheta inhibitors: part II.
We previously reported that a 3-pyridinecarbonitrile analog with a furan substituent at C-5 and a 4-methylindol-5-ylamino substituent at C-4, 1, was a potent inhibitor of PKCtheta (IC50=4.5 nM). Replacement of the C-5 furan ring of 1 with bicyclic heteroaryl rings, led to compounds with significantly improved potency against PKCtheta. Analog 6b with a 4-methylindol-5-ylamino group at C-4 and a 5-[(4-methylpiperazin-1-yl)methyl]-1-benzofuran-2-yl group at C-5 had an IC50 value of 0.28 nM for the inhibition of PKCtheta.
Prashad
Amar S
AS
Wyeth Research, Chemical Sciences, 401 N. Middletown Road, Pearl River, NY 10965, United States. prashaa@wyeth.com
Wang
Daniel
D
Subrath
Joan
J
Wu
Biqi
B
Lin
Melissa
M
Zhang
Mei-Yi
MY
Kagan
Natasha
N
Lee
Julie
J
Yang
Xiaoke
X
Brennan
Agnes
A
Chaudhary
Divya
D
Xu
Xin
X
Leung
Louis
L
Wang
Jack
J
Boschelli
Diane H
DH
D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; 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; D051381:Rats; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D000631:Aminopyridines; D001572:Benzofurans; D007376:Interleukin-2; D007527:Isoenzymes; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta