title: Identification, characterization and initial hit-to-lead optimization of a series of 4-arylamino-3-pyridinecarbonitrile as protein kinase C theta (PKCtheta) inhibitors.
abstract: The protein kinase C (PKC) family of serine/threonine kinases is implicated in a wide variety of cellular processes. The PKC theta (PKCtheta) isoform is involved in TCR signal transduction and T cell activation and regulates T cell mediated diseases, including lung inflammation and airway hyperresponsiveness. Thus inhibition of PKCtheta enzyme activity by a small molecule represents an attractive strategy for the treatment of asthma. A PKCtheta high-throughput screening (HTS) campaign led to the identification of 4-(3-bromophenylamino)-5-(3,4-dimethoxyphenyl)-3-pyridinecarbonitrile 4a, a low microM ATP competitive PKCtheta inhibitor. Structure based hit-to-lead optimization led to the identification of 5-(3,4-dimethoxyphenyl)-4-(1H-indol-5-ylamino)-3-pyridinecarbonitrile 4p, a 70 nM PKCtheta inhibitor. Compound 4p was selective for inhibition of novel PKC isoforms over a panel of 21 serine/threonine, tyrosine, and phosphoinositol kinases, in addition to the conventional and atypical PKCs, PKCbeta, and PKCzeta, respectively. Compound 4p also inhibited IL-2 production in antiCD3/anti-CD28 activated T cells enriched from splenocytes.
authors.affiliation: Chemical and Screening Sciences, Wyeth Research, Pearl River, New York 10965, USA. coledc@wyeth.com
authors.forename: Derek C
authors.initials: DC
authors.lastname: Cole
authors.forename: Magda
authors.initials: M
authors.lastname: Asselin
authors.forename: Agnes
authors.initials: A
authors.lastname: Brennan
authors.forename: Robert
authors.initials: R
authors.lastname: Czerwinski
authors.forename: John W
authors.initials: JW
authors.lastname: Ellingboe
authors.forename: Lori
authors.initials: L
authors.lastname: Fitz
authors.forename: Rita
authors.initials: R
authors.lastname: Greco
authors.forename: Xinyi
authors.initials: X
authors.lastname: Huang
authors.forename: Diane
authors.initials: D
authors.lastname: Joseph-McCarthy
authors.forename: Michael F
authors.initials: MF
authors.lastname: Kelly
authors.forename: Matthew
authors.initials: M
authors.lastname: Kirisits
authors.forename: Julie
authors.initials: J
authors.lastname: Lee
authors.forename: Yuanhong
authors.initials: Y
authors.lastname: Li
authors.forename: Paul
authors.initials: P
authors.lastname: Morgan
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Stock
authors.forename: Désirée H H
authors.initials: DH
authors.lastname: Tsao
authors.forename: Allan
authors.initials: A
authors.lastname: Wissner
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Yang
authors.forename: Divya
authors.initials: D
authors.lastname: Chaudhary
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000187:drug effects; 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*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D007211:Indoles; D007376:Interleukin-2; D007527:Isoenzymes; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta