title: Kinase array design, back to front: biaryl amides.
abstract: New kinase inhibitors can be found by synthesis of targeted arrays of compounds designed using system-based knowledge as well as through screening focused or diverse compounds. Most array strategies aim to add functionality to a fragment that binds in the purine subpocket of the ATP-site. Here, an alternative pharmacophore-guided array approach is described which set out to discover novel purine subpocket-binding groups. Results are shown for p38alpha and cFMS kinase, for which multiple distinct series with nanomolar potency were discovered. Some of the compounds showed potency in cell-based assays and good pharmacokinetic properties.
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Baldwin
authors.forename: Paul
authors.initials: P
authors.lastname: Bamborough
authors.forename: Claudine G
authors.initials: CG
authors.lastname: Haslam
authors.forename: Suchete S
authors.initials: SS
authors.lastname: Hunjan
authors.forename: Tim
authors.initials: T
authors.lastname: Longstaff
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Mooney
authors.forename: Shila
authors.initials: S
authors.lastname: Patel
authors.forename: Jo
authors.initials: J
authors.lastname: Quinn
authors.forename: Don O
authors.initials: DO
authors.lastname: Somers
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D020128:Inhibitory Concentration 50; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D006573:Heterocyclic Compounds, 1-Ring; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D048308:Mitogen-Activated Protein Kinase 14