title: Photochemical preparation of a pyridone containing tetracycle: a Jak protein kinase inhibitor.
abstract: Jak3 is a protein tyrosine kinase that is associated with the shared gamma chain of receptors for cytokines IL2, IL4, IL7, IL9, and IL13. We have discovered that a pyridone-containing tetracycle (6) may be prepared from trisubstituted imidazole (5) in high yield by irradiation with >350 nm light. Compound 6 inhibits Jak3 with K(I)=5 nM; it also inhibits Jak family members Tyk2 and Jak2 with IC(50)=1 nM and murine Jak1with IC(50)=15 nM. Compound 6 was tested as an inhibitor of 21 other protein kinases; it inhibited these kinases with IC(50)s ranging from 130 nM to >10 microM. Compound 6 also blocks IL2 and IL4 dependent proliferation of CTLL cells and inhibits the phosphorylation of STAT5 (an in vivo substrate of the Jak family) as measured by Western blotting.
authors.affiliation: Merck Research Laboratories, Merck & Co., 80M-127, PO Box 2000, Rahway, NJ 07065-0900, USA. jed_thompson@merck.com
authors.forename: James E
authors.initials: JE
authors.lastname: Thompson
authors.forename: Rose M
authors.initials: RM
authors.lastname: Cubbon
authors.forename: Richard T
authors.initials: RT
authors.lastname: Cummings
authors.forename: Linda S
authors.initials: LS
authors.lastname: Wicker
authors.forename: Robert
authors.initials: R
authors.lastname: Frankshun
authors.forename: Barry R
authors.initials: BR
authors.lastname: Cunningham
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Cameron
authors.forename: Peter T
authors.initials: PT
authors.lastname: Meinke
authors.forename: Nigel
authors.initials: N
authors.lastname: Liverton
authors.forename: Youmin
authors.initials: Y
authors.lastname: Weng
authors.forename: Julie A
authors.initials: JA
authors.lastname: DeMartino
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D053616:Janus Kinase 3; D051379:Mice; D008894:Milk Proteins; D010766:Phosphorylation; D010777:Photochemistry; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000737:chemistry*; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D008894:Milk Proteins; D011728:Pyridones; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D015847:Interleukin-4; D011505:Protein-Tyrosine Kinases; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3