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.

DC120, a Novel and Potent Inhibitor of AKT Kinase, Induces Tumor Cell Apoptosis and Suppresses Tumor Growth

“…In the present study, we analyzed the crystal structures of the published ATP-competitive AKT inhibitors bound to AKT kinases (Lin et al, 2006;Zhu et al, 2007;Seefeld et al, 2009;McHardy et al, 2010) and optimized the screened hit compounds to a series of 2-(methylaminopyrimidinyl) thiazole-5-carboxamide derivatives (Chang et al, 2012). We screened out (S)-N-(1-amino-3-(2,4-dichlorophenyl)propan-2-yl)-2-(2-(methylamino)pyrimidin-4-yl)thiazole-5-carboxamide (DC120) from these compounds by a fluorescence resonance energy transfer-based ZЈ-LYTE assay (EC 50 ϭ 153 nM) and focused on the antitumor activity of this potent compound.…”

Antitumor and anti-angiogenic activities of Scutellaria barbata extracts in vitro are partially mediated by inhibition of Akt/protein kinase B

“…This Akt inhibition was found to be specific as PI3K kinase, the upstream kinase of Akt, was not inhibited, whereas the levels of phosphorylated Bad and FHKR, the two downstream targets of Akt, changed as the level of Akt changed. It is known that certain synthetic small-molecule Akt inhibitors are associated with unexpected toxicities, such as increased blood glucose and insulin levels, hyperglycemia, and acute systemic hypotension (36)(37)(38). Thus, S. barbata may be a suitable alternative source to isolate small molecules for use as Akt kinase inhibitors, as this herb has been safely used for a long time.…”

A comprehensive structure–activity analysis of protein kinase B-alpha (Akt1) inhibitors

“…The binding affinity (IC 50 ranging 0.16 nm to 126 mm) data of 265 molecules was collected from the various literature reports [9,10,[18][19][20][21][22][23][24][25][26] and converted to pIC 50 for the QSAR analysis. Additionally, the literature also reports the binding domain (PH or kinase) for all these molecules.…”

“…For the present study, we gathered a chemically diverse set of Akt1 inhibitors available in various literature reports [9,10,[18][19][20][21][22][23][24][25][26]. To gain deeper insights into the structural requirements for Akt1 inhibition and develop quantitative models for the development of new Akt1 inhibitors, we utilized the recently developed method of Group-Based QSAR [16].…”