Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase B/Akt inhibitors with reduced hypotension.
Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.
Zhu
Gui-Dong
GD
Cancer Research, Preclinical Safety, Structural Biology, Integrative Pharmacology, GPRD, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6101, USA. gui-dong.zhu@abbott.com
Gandhi
Viraj B
VB
Gong
Jianchun
J
Thomas
Sheela
S
Woods
Keith W
KW
Song
Xiaohong
X
Li
Tongmei
T
Diebold
R Bruce
RB
Luo
Yan
Y
Liu
Xuesong
X
Guan
Ran
R
Klinghofer
Vered
V
Johnson
Eric F
EF
Bouska
Jennifer
J
Olson
Amanda
A
Marsh
Kennan C
KC
Stoll
Vincent S
VS
Mamo
Mulugeta
M
Polakowski
James
J
Campbell
Thomas J
TJ
Martin
Ruth L
RL
Gintant
Gary A
GA
Penning
Thomas D
TD
Li
Qun
Q
Rosenberg
Saul H
SH
Giranda
Vincent L
VL
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004285:Dogs; D007022:Hypotension / Q000139:chemically induced*; D007191:Indazoles / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology; D011720:Pyrazoles / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D011725:Pyridines / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C531038:1-(5-(3-methyl-1H-pyrazolo(3,4-c)pyridin-5-yl)pyridin-3-yloxy)-3-(3-(trifluoromethyl)phenyl)propan-2-amine; D007191:Indazoles; D011720:Pyrazoles; D011725:Pyridines; D051057:Proto-Oncogene Proteins c-akt