title: The development of novel 1,2-dihydro-pyrimido[4,5-c]pyridazine based inhibitors of lymphocyte specific kinase (Lck).
abstract: 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.
authors.affiliation: Procter and Gamble Pharmaceuticals, Health Care Research Center, Mason, OH 45040, USA. sabat.mp@pg.com
authors.forename: Mark
authors.initials: M
authors.lastname: Sabat
authors.forename: John C
authors.initials: JC
authors.lastname: Vanrens
authors.forename: Todd A
authors.initials: TA
authors.lastname: Brugel
authors.forename: Jennifer
authors.initials: J
authors.lastname: Maier
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Laufersweiler
authors.forename: Adam
authors.initials: A
authors.lastname: Golebiowski
authors.forename: Biswanath
authors.initials: B
authors.lastname: De
authors.forename: Vijayasurian
authors.initials: V
authors.lastname: Easwaran
authors.forename: Lily C
authors.initials: LC
authors.lastname: Hsieh
authors.forename: Jeff
authors.initials: J
authors.lastname: Rosegen
authors.forename: Steve
authors.initials: S
authors.lastname: Berberich
authors.forename: Eric
authors.initials: E
authors.lastname: Suchanek
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Janusz
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D011724:Pyridazines; D011743:Pyrimidines; D012263:Ribonucleosides; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)