Discovery of A-770041, a src-family selective orally active lck inhibitor that prevents organ allograft rejection.
We describe the identification, SAR, and pharmacology of the src-family selective lck inhibitor A-770041 that prolongs the survival of major histocompatibility mismatched allografts in models of solid organ transplant rejection for greater than 65 days.
Burchat
Andrew
A
Abbott Bioresearch Center, 100 Research Drive, Worcester, MA 01605-5314, USA.
Borhani
David W
DW
Calderwood
David J
DJ
Hirst
Gavin C
GC
Li
Biqin
B
Stachlewitz
Robert F
RF
D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006084:Graft Rejection / Q000517:prevention & control*; D016027:Heart Transplantation / Q000379:methods; D006801:Humans; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors*; D008285:Major Histocompatibility Complex; D008956:Models, Chemical; D008958:Models, Molecular; D004364:Pharmaceutical Preparations; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D013997:Time Factors; D014184:Transplantation, Homologous / Q000379:methods; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
C505452:1-methyl-1H-indole-2-carboxylic acid (4-(1-(4-(4-acetylpiperazin-1-yl)cyclohexyl)-4-amino-1H-pyrazolo(3,4-d)pyrimidin-3-yl)-2-methoxyphenyl)amide; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D004364:Pharmaceutical Preparations; D011720:Pyrazoles; D011743:Pyrimidines; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases