New pyrazolo[1,5a]pyrimidines as orally active inhibitors of Lck.
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.
Gommermann
Nina
N
Novartis Institute of Biomedical Research, Forum 1, Novartis Campus, Basel, Switzerland. nina.gommermann@novartis.com
Buehlmayer
Peter
P
von Matt
Anette
A
Breitenstein
Werner
W
Masuya
Keiichi
K
Pirard
Bernard
B
Furet
Pascal
P
Cowan-Jacob
Sandra W
SW
Weckbecker
Gisbert
G
D000284:Administration, Oral; D000818:Animals; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D007376:Interleukin-2; D011743:Pyrimidines; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)