title: 5-Vinyl-3-pyridinecarbonitrile inhibitors of PKCtheta: optimization of enzymatic and functional activity.
abstract: PKCtheta is a serine/threonine kinase involved in the regulation of IL2 production in T cells. It has recently become an attractive therapeutic target for a variety of immunological disorders. We describe the optimization of the enzymatic and cellular potency of a series of 5-vinyl-3-pyridinecarbonitrile inhibitors of PKCtheta. A binding model was developed that explains much of the SAR observed for this series, including the enzymatic potency observed for 19. An analysis of functional potency against various physiochemical parameters suggests that cellular potency is correlated with LogD(7.4), but not with cLogP, PAMPA permeability, or TPSA.
authors.affiliation: Wyeth Research, Medicinal Chemistry, 401 N. Middletown Rd., Pearl River, NY 10965, United States. tumeyn@wyeth.com
authors.forename: L Nathan
authors.initials: LN
authors.lastname: Tumey
authors.forename: Niala
authors.initials: N
authors.lastname: Bhagirath
authors.forename: Agnes
authors.initials: A
authors.lastname: Brennan
authors.forename: Natasja
authors.initials: N
authors.lastname: Brooijmans
authors.forename: Julie
authors.initials: J
authors.lastname: Lee
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Yang
authors.forename: Diane H
authors.initials: DH
authors.lastname: Boschelli
mesh_terms: D000818:Animals; D003198:Computer Simulation; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; 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; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D014753:Vinyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D007527:Isoenzymes; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D014753:Vinyl Compounds; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta