title: N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of Lck: indazoles as phenol isosteres with improved pharmacokinetics.
abstract: 2,4-Dianilino pyrimidines are well-known inhibitors of tyrosine kinases including lymphocyte specific kinase (Lck). Structure-activity relationships at the 4-position are discussed and rationalised. Examples bearing a 2-methyl-5-hydroxyaniline substituent at the 4-position were especially potent but showed poor oral pharmacokinetics. Replacement of this substituent by 4-amino(5-methyl-1H-indazole) yielded compounds with comparable enzyme potency and improved pharmacokinetic properties.
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Paul.A.Bamborough@gsk.com
authors.forename: Paul
authors.initials: P
authors.lastname: Bamborough
authors.forename: Richard M
authors.initials: RM
authors.lastname: Angell
authors.forename: Inder
authors.initials: I
authors.lastname: Bhamra
authors.forename: David
authors.initials: D
authors.lastname: Brown
authors.forename: James
authors.initials: J
authors.lastname: Bull
authors.forename: John A
authors.initials: JA
authors.lastname: Christopher
authors.forename: Anthony W J
authors.initials: AW
authors.lastname: Cooper
authors.forename: Lynsey H
authors.initials: LH
authors.lastname: Fazal
authors.forename: Ilaria
authors.initials: I
authors.lastname: Giordano
authors.forename: Lucy
authors.initials: L
authors.lastname: Hind
authors.forename: Vipulkumar K
authors.initials: VK
authors.lastname: Patel
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Ranshaw
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Sims
authors.forename: Philip A
authors.initials: PA
authors.lastname: Skone
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Smith
authors.forename: Emma
authors.initials: E
authors.lastname: Vickerstaff
authors.forename: Melanie
authors.initials: M
authors.lastname: Washington
mesh_terms: D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D007191:Indazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors*; D008958:Models, Molecular
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)