ABSTRACT
The synthesis and evaluation of tetrasubstituted aminopyridines, bearing novel azaindazole hinge binders, as potent AKT inhibitors are described. Compound 14c was identified as a potent AKT inhibitor that demonstrated reduced CYP450 inhibition and an improved developability profile compared to those of previously described trisubstituted pyridines. It also displayed dose-dependent inhibition of both phosphorylation of GSK3beta and tumor growth in a BT474 tumor xenograft model in mice.
Subject(s)
Aminopyridines/chemistry , Cytochrome P-450 Enzyme System/metabolism , Ether-A-Go-Go Potassium Channels/metabolism , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Pyrazines/chemistry , Pyridines/chemistry , Aminopyridines/chemical synthesis , Aminopyridines/pharmacokinetics , Animals , Cell Line, Tumor , Dogs , ERG1 Potassium Channel , Glycogen Synthase Kinase 3/antagonists & inhibitors , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Haplorhini , Humans , Mice , Phosphorylation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Proto-Oncogene Proteins c-akt/metabolism , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , Rats , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
[reaction: see text] The total synthesis of the new cytotoxic marine macrolide (+)-dactylolide (1) has been achieved in nine steps from known vinyl bromide (-)-AB. In addition, (+)-zampanolide (2) has been converted to (+)-dactylolide (1) via thermolysis.
Subject(s)
Antineoplastic Agents/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Lactones/chemical synthesis , Porifera/chemistry , Animals , Indicators and Reagents , Macrolides/chemistry , Magnetic Resonance Spectroscopy , Mass SpectrometryABSTRACT
Overexpression of AKT has an antiapoptotic effect in many cell types, and expression of dominant negative AKT blocks the ability of a variety of growth factors to promote survival. Therefore, inhibitors of AKT kinase activity might be useful as monotherapy for the treatment of tumors with activated AKT. Herein, we describe our lead optimization studies culminating in the discovery of compound 3g (GSK690693). Compound 3g is a novel ATP competitive, pan-AKT kinase inhibitor with IC 50 values of 2, 13, and 9 nM against AKT1, 2, and 3, respectively. An X-ray cocrystal structure was solved with 3g and the kinase domain of AKT2, confirming that 3g bound in the ATP binding pocket. Compound 3g potently inhibits intracellular AKT activity as measured by the inhibition of the phosphorylation levels of GSK3beta. Intraperitoneal administration of 3g in immunocompromised mice results in the inhibition of GSK3beta phosphorylation and tumor growth in human breast carcinoma (BT474) xenografts.
Subject(s)
Oxadiazoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Animals , Female , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mice , Mice, SCID , Models, Molecular , Oxadiazoles/chemistry , Oxadiazoles/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Substrate SpecificityABSTRACT
A novel benzimidazole series of small-molecule thrombopoietin receptor agonists has been discovered. Herein, we discuss the preliminary exploration of structure-activity relationships within this chemotype.
Subject(s)
Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Receptors, Cytokine/agonists , Receptors, Cytokine/metabolism , Thrombopoietin/metabolism , Acids/chemistry , Benzimidazoles/chemical synthesis , Molecular Structure , Naphthols/chemistry , Structure-Activity RelationshipABSTRACT
The first total syntheses of (+)-zampanolide (1) and (+)-dactylolide (2), members of a new class of tumor cell growth inhibitory macrolides, have been achieved. Key features of the unified synthetic scheme included the stereocontrolled construction of the cis-2,6-disubstituted tetrahydropyran via a modified Petasis-Ferrier rearrangement, a highly convergent assembly of the macrocyclic domain, and, in the case of zampanolide, a Curtius rearrangement/acylation tactic to install the N-acyl hemiaminal. The complete relative and absolute stereochemistries for both (+)-zampanolide and (+)-dactylolide were also assigned, albeit tentatively in the case of (+)-zampanolide (1).