title: 4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: potent and selective p70S6 kinase inhibitors.
abstract: We report herein the design and synthesis of 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-amine derivatives as inhibitors of p70S6 kinase. Screening hits containing the 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine scaffold were optimized for p70S6K potency and selectivity against related kinases. Structure-based design employing an active site homology model derived from PKA led to the preparation of benzimidazole 5-substituted compounds 26 and 27 as highly potent inhibitors (K(i) <1nM) of p70S6K, with >100-fold selectivity against PKA, ROCK and GSK3.
authors.affiliation: Vertex Pharmaceuticals, Inc., 130 Waverly Street, Cambridge, MA 02139, USA.
authors.forename: Upul
authors.initials: U
authors.lastname: Bandarage
authors.forename: Brian
authors.initials: B
authors.lastname: Hare
authors.forename: Jonathan
authors.initials: J
authors.lastname: Parsons
authors.forename: Ly
authors.initials: L
authors.lastname: Pham
authors.forename: Craig
authors.initials: C
authors.lastname: Marhefka
authors.forename: Guy
authors.initials: G
authors.lastname: Bemis
authors.forename: Qing
authors.initials: Q
authors.lastname: Tang
authors.forename: Cameron Stuver
authors.initials: CS
authors.lastname: Moody
authors.forename: Steve
authors.initials: S
authors.lastname: Rodems
authors.forename: Sundeep
authors.initials: S
authors.lastname: Shah
authors.forename: Chris
authors.initials: C
authors.lastname: Adams
authors.forename: Jose
authors.initials: J
authors.lastname: Bravo
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Charonnet
authors.forename: Vladimir
authors.initials: V
authors.lastname: Savic
authors.forename: Jon H
authors.initials: JH
authors.lastname: Come
authors.forename: Jeremy
authors.initials: J
authors.lastname: Green
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D054460:rho-Associated Kinases; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; D038362:Glycogen Synthase Kinase 3