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

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Thompson JE, Cubbon RM, Cummings RT, Wicker LS, Frankshun R, Cunningham BR, Cameron PM, Meinke PT, Liverton N, Weng Y, DeMartino JA

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

Bioorg Med Chem Lett. 2002 Apr 22;12(8):1219-23.

PubMed ID

11934592 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
2-tert-butyl-9-fluoro-1,6-dihydrobenzo[h]imidazo[4,5-f]isoquinolin-7-one	Non-receptor tyrosine-protein kinase TYK2	IC 50 (nM)	1	N/A	N/A	Details
2-tert-butyl-9-fluoro-1,6-dihydrobenzo[h]imidazo[4,5-f]isoquinolin-7-one	Tyrosine-protein kinase JAK2	IC 50 (nM)	1	N/A	N/A	Details
2-tert-butyl-9-fluoro-1,6-dihydrobenzo[h]imidazo[4,5-f]isoquinolin-7-one	Tyrosine-protein kinase JAK3	IC 50 (nM)	5	N/A	N/A	Details