2,3,5-Trisubstituted pyridines as selective AKT inhibitors-Part I: Substitution at 2-position of the core pyridine for ROCK1 selectivity.
2,3,5-Trisubstituted pyridines have been designed as potent AKT inhibitors that are selective against ROCK1 based on the comparison between AKT and ROCK1 structures. Substitution at the 2-position of the core pyridine is the key element to provide selectivity against ROCK1. An X-ray co-crystal structure of 9p in PKA supports the proposed rationale of ROCK1 selectivity.
Lin
Hong
H
Oncology Medicinal Chemistry, GlaxoSmithKline, 1250 S. Collegeville, Rd., Collegeville, PA 19426, United States. hong.2.lin@gsk.com
Yamashita
Dennis S
DS
Zeng
Jin
J
Xie
Ren
R
Wang
Wenyong
W
Nidarmarthy
Sirishkumar
S
Luengo
Juan I
JI
Rhodes
Nelson
N
Knick
Victoria B
VB
Choudhry
Anthony E
AE
Lai
Zhihong
Z
Minthorn
Elisabeth A
EA
Strum
Susan L
SL
Wood
Edgar R
ER
Elkins
Patricia A
PA
Concha
Nestor O
NO
Heerding
Dirk A
DA
D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D011725:Pyridines; D051057:Proto-Oncogene Proteins c-akt; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases