The development of novel 1,2-dihydro-pyrimido[4,5-c]pyridazine based inhibitors of lymphocyte specific kinase (Lck).
This communication details the synthesis, biological activity, and proposed binding mode of a novel class of tri-cyclic derivatives of 1,2-dihydro-pyrimido[4,5-c]pyridazines 1 and 2. The most potent analogs disclosed showed low nanomolar activity for the inhibition of Lck kinase.
Sabat
Mark
M
Procter and Gamble Pharmaceuticals, Health Care Research Center, Mason, OH 45040, USA. sabat.mp@pg.com
Vanrens
John C
JC
Brugel
Todd A
TA
Maier
Jennifer
J
Laufersweiler
Matthew J
MJ
Golebiowski
Adam
A
De
Biswanath
B
Easwaran
Vijayasurian
V
Hsieh
Lily C
LC
Rosegen
Jeff
J
Berberich
Steve
S
Suchanek
Eric
E
Janusz
Michael J
MJ
D015195:Drug Design; D004345:Drug Industry / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors*; D008214:Lymphocytes / Q000378:metabolism; D008956:Models, Chemical; D008958:Models, Molecular; D011724:Pyridazines / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D012263:Ribonucleosides / Q000737:chemistry*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D011724:Pyridazines; D011743:Pyrimidines; D012263:Ribonucleosides; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)