Pyrazolo[3,4-d]pyrimidines containing an extended 3-substituent as potent inhibitors of Lck -- a selectivity insight.
A series of para-substituted 3-phenyl pyrazolopyrimidines was synthesized and evaluated as inhibitors of lck. The nature of the substitution affected enzyme selectivity and potency for lck, src, kdr, and tie-2. The para-phenoxyphenyl analogue 2 is an orally active lck inhibitor with a bioavailability of 69% and exhibits an extended duration of action in animal models of T cell inhibition.
Burchat
Andrew F
AF
Abbott Bioresearch Center, 100 Research Drive, Worcester, MA 01605-5314, USA.
Calderwood
David J
DJ
Friedman
Michael M
MM
Hirst
Gavin C
GC
Li
Biqin
B
Rafferty
Paul
P
Ritter
Kurt
K
Skinner
Barbara S
BS
D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors*; D008297:Male; D008958:Models, Molecular; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D011743:Pyrimidines; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)