title: Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase B/Akt inhibitors with reduced hypotension.
abstract: 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.
authors.affiliation: 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
authors.forename: Gui-Dong
authors.initials: GD
authors.lastname: Zhu
authors.forename: Viraj B
authors.initials: VB
authors.lastname: Gandhi
authors.forename: Jianchun
authors.initials: J
authors.lastname: Gong
authors.forename: Sheela
authors.initials: S
authors.lastname: Thomas
authors.forename: Keith W
authors.initials: KW
authors.lastname: Woods
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Song
authors.forename: Tongmei
authors.initials: T
authors.lastname: Li
authors.forename: R Bruce
authors.initials: RB
authors.lastname: Diebold
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Xuesong
authors.initials: X
authors.lastname: Liu
authors.forename: Ran
authors.initials: R
authors.lastname: Guan
authors.forename: Vered
authors.initials: V
authors.lastname: Klinghofer
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bouska
authors.forename: Amanda
authors.initials: A
authors.lastname: Olson
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Stoll
authors.forename: Mulugeta
authors.initials: M
authors.lastname: Mamo
authors.forename: James
authors.initials: J
authors.lastname: Polakowski
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Campbell
authors.forename: Ruth L
authors.initials: RL
authors.lastname: Martin
authors.forename: Gary A
authors.initials: GA
authors.lastname: Gintant
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Penning
authors.forename: Qun
authors.initials: Q
authors.lastname: Li
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Giranda
mesh_terms: 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
chemical_list: 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