Photochemical preparation of a pyridone containing tetracycle: A Jak protein kinase inhibitor

Jak3 is a protein tyrosine kinase that is associated with the shared 7 chain of receptors for cytokines IL2, IL4, IL7, IL9, and IL13. We have discovered that a pyridone-containing tetracycle (6) may be prepared front 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 IC50 = 1 nM and murine Jak 1 with IC50 = 15 nM. Compound 6 vas tested as an inhibitor of 21 other protein kinases: it inhibited these kinases with IC(50)s ranging from 130 nM to > 10 muM. 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. (C) 2002 Elsevier Science Ltd. All rights reserved.