Discovery and Optimization of Potent, Selective, and in Vivo Efficacious 2-Aryl Benzimidazole BCATm Inhibitors.
To identify BCATm inhibitors suitable for in vivo study, Encoded Library Technology (ELT) was used to affinity screen a 117 million member benzimidazole based DNA encoded library, which identified an inhibitor series with both biochemical and cellular activities. Subsequent SAR studies led to the discovery of a highly potent and selective compound, 1-(3-(5-bromothiophene-2-carboxamido)cyclohexyl)-N-methyl-2-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamide (8b) with much improved PK properties. X-ray structure revealed that 8b binds to the active site of BACTm in a unique mode via multiple H-bond and van der Waals interactions. After oral administration, 8b raised mouse blood levels of all three branched chain amino acids as a consequence of BCATm inhibition.
Platform of Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Hongfeng
H
Deng
Platform of Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Jingye
J
Zhou
Platform of Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Flora
F
Sundersingh
Platform of Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Jeffrey A
JA
Messer
Medicines Research Centre, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Herts, SG1 2NY, U.K.
Donald O
DO
Somers
Centre de Recherche, GlaxoSmithKline , Les Ulis, 25,27 Avenue du Québec, 91140 Villebon sur Yvette, France.
Myriam
M
Ajakane
Platform of Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Christopher C
CC
Arico-Muendel
Medicines Research Centre, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Herts, SG1 2NY, U.K.
Arthur
A
Beljean
Platform of Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Svetlana L
SL
Belyanskaya
Medicines Research Centre, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Herts, SG1 2NY, U.K.
Ryan
R
Bingham
Chemistry Department, Northeastern University , Boston, Massachusetts 02115, United States.
Emily
E
Blazensky
Centre de Recherche, GlaxoSmithKline , Les Ulis, 25,27 Avenue du Québec, 91140 Villebon sur Yvette, France.
Anne-Benedicte
AB
Boullay
Centre de Recherche, GlaxoSmithKline , Les Ulis, 25,27 Avenue du Québec, 91140 Villebon sur Yvette, France.
Eric
E
Boursier
Platform of Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Jing
J
Chai
Medicines Research Centre, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Herts, SG1 2NY, U.K.
Paul
P
Carter
Medicines Research Centre, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Herts, SG1 2NY, U.K.
Chun-Wa
CW
Chung
Centre de Recherche, GlaxoSmithKline , Les Ulis, 25,27 Avenue du Québec, 91140 Villebon sur Yvette, France.
Alain
A
Daugan
Platform of Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Yun
Y
Ding
Centre de Recherche, GlaxoSmithKline , Les Ulis, 25,27 Avenue du Québec, 91140 Villebon sur Yvette, France.
Kenny
K
Herry
Medicines Research Centre, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Herts, SG1 2NY, U.K.
Clare
C
Hobbs
Chemistry Department, Northeastern University , Boston, Massachusetts 02115, United States.
Eric
E
Humphries
Platform of Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Christopher
C
Kollmann
Centre de Recherche, GlaxoSmithKline , Les Ulis, 25,27 Avenue du Québec, 91140 Villebon sur Yvette, France.
Van Loc
VL
Nguyen
Centre de Recherche, GlaxoSmithKline , Les Ulis, 25,27 Avenue du Québec, 91140 Villebon sur Yvette, France.
Edwige
E
Nicodeme
Medicines Research Centre, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Herts, SG1 2NY, U.K.
Sarah E
SE
Smith
Centre de Recherche, GlaxoSmithKline , Les Ulis, 25,27 Avenue du Québec, 91140 Villebon sur Yvette, France.
Nerina
N
Dodic
Centre de Recherche, GlaxoSmithKline , Les Ulis, 25,27 Avenue du Québec, 91140 Villebon sur Yvette, France.
Nicolas
N
Ancellin
2-aryl benzimidazole; BCATm; DNA Encoded Library; ELT; branched chain amino acids (BCAAs)