New pyrazolo[1,5a]pyrimidines as orally active inhibitors of Lck

The preparation of pyrazolo[1,5a]pyrimidines and their evaluation as inhibitors of lymphocyte-specific kinase (Lck) both in vitro and in vivo is described. A novel series of pyrazolo[1,5a]pyrimidines was optimized to target lymphocyte-specific kinase (Lck). An efficient synthetic route was developed...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-06, Vol.20 (12), p.3628-3631
Hauptverfasser:	Gommermann, Nina, Buehlmayer, Peter, von Matt, Anette, Breitenstein, Werner, Masuya, Keiichi, Pirard, Bernard, Furet, Pascal, Cowan-Jacob, Sandra W., Weckbecker, Gisbert
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Humans Immunomodulators Interleukin-2 - metabolism Lymphocyte Activation - drug effects Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - antagonists & inhibitors Medical sciences Mice Microsomes, Liver - metabolism Pharmacology. Drug treatments Pyrimidines - pharmacology Rats Structure-Activity Relationship
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Zusammenfassung:	The preparation of pyrazolo[1,5a]pyrimidines and their evaluation as inhibitors of lymphocyte-specific kinase (Lck) both in vitro and in vivo is described. A novel series of pyrazolo[1,5a]pyrimidines was optimized to target lymphocyte-specific kinase (Lck). An efficient synthetic route was developed and SAR studies toward activity and selectivity are described, leading to Lck inhibitors with enzymatic, cellular and in vivo potency.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.04.112