4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: potent and selective p70S6 kinase inhibitors.
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.
Bandarage
Upul
U
Vertex Pharmaceuticals, Inc., 130 Waverly Street, Cambridge, MA 02139, USA.
Hare
Brian
B
Parsons
Jonathan
J
Pham
Ly
L
Marhefka
Craig
C
Bemis
Guy
G
Tang
Qing
Q
Moody
Cameron Stuver
CS
Rodems
Steve
S
Shah
Sundeep
S
Adams
Chris
C
Bravo
Jose
J
Charonnet
Emmanuelle
E
Savic
Vladimir
V
Come
Jon H
JH
Green
Jeremy
J
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
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