title: C-5 substituted heteroaryl-3-pyridinecarbonitriles as PKCtheta inhibitors: part II.
abstract: 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.
authors.affiliation: Wyeth Research, Chemical Sciences, 401 N. Middletown Road, Pearl River, NY 10965, United States. prashaa@wyeth.com
authors.forename: Amar S
authors.initials: AS
authors.lastname: Prashad
authors.forename: Daniel
authors.initials: D
authors.lastname: Wang
authors.forename: Joan
authors.initials: J
authors.lastname: Subrath
authors.forename: Biqi
authors.initials: B
authors.lastname: Wu
authors.forename: Melissa
authors.initials: M
authors.lastname: Lin
authors.forename: Mei-Yi
authors.initials: MY
authors.lastname: Zhang
authors.forename: Natasha
authors.initials: N
authors.lastname: Kagan
authors.forename: Julie
authors.initials: J
authors.lastname: Lee
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Yang
authors.forename: Agnes
authors.initials: A
authors.lastname: Brennan
authors.forename: Divya
authors.initials: D
authors.lastname: Chaudhary
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Louis
authors.initials: L
authors.lastname: Leung
authors.forename: Jack
authors.initials: J
authors.lastname: Wang
authors.forename: Diane H
authors.initials: DH
authors.lastname: Boschelli
mesh_terms: 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
chemical_list: 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