Pyrrolo[2,3- d]pyrimidines containing diverse N-7 substituents as potent inhibitors of Lck

• Published in: Bioorganic & medicinal chemistry letters Vol. 12; no. 12; pp. 1683 - 1686
• Main Authors: Calderwood, David J., Johnston, David N., Munschauer, Rainer, Rafferty, Paul
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 17.06.2002; Elsevier
• Subjects: Biological and medical sciences; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Immunomodulators; Jurkat Cells; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - analysis; Medical sciences; Pharmacology. Drug treatments; Pyrimidines - chemistry; Pyrimidines - pharmacology; Intraperitoneal administration; Intravenous administration; Nitrogen heterocycle; Signal transduction; Interleukin 2; Structure activity relation; T-Lymphocyte; Bicyclic compound; Inhibition; Chemical synthesis; Protein-tyrosine kinase; Human; Ether; Enzyme; Transferases; Rodentia; Benzene derivatives; Cytokine; Oral administration; Enzyme inhibitor; Bioavailability; In vitro; Immunomodulator; Whole blood; In vivo; Vertebrata; Mammalia; Mouse; Animal; Piperazine derivatives; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(02)00195-6

A series of pyrrolo[2,3- d]pyrimidines was synthesized and evaluated as inhibitors of Lck. Lck accommodates a diverse set of substituents at N-7. Altering the substituent at N-7 provided compound 13, an orally available lck inhibitor which inhibited TCR mediated IL-2 production after oral dosing. Optimization of the N-7 position resulted in compound 13, a potent and orally active lck inhibitor.