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

  • Bioorg Med Chem Lett. 2002 Apr 22;12(8):1219-23. doi: 10.1016/s0960-894x(02)00106-3.
James E Thompson  1 ,  Rose M Cubbon ,  Richard T Cummings ,  Linda S Wicker ,  Robert Frankshun ,  Barry R Cunningham ,  Patricia M Cameron ,  Peter T Meinke ,  Nigel Liverton ,  Youmin Weng ,  Julie A DeMartino
Affiliations
  • 1. Merck Research Laboratories, Merck & Co., 80M-127, PO Box 2000, Rahway, NJ 07065-0900, USA. [email protected]
PMID: 11934592 DOI: 10.1016/s0960-894x(02)00106-3
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.

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