ABSTRACT
Activation of the PI3K/Akt/mTOR kinase pathway is associated with human cancers. A dual p70S6K/Akt inhibitor is sufficient to inhibit strong tumor growth and to block negative impact of the compensatory Akt feedback loop activation. A scaffold docking strategy based on an existing quinazoline carboxamide series identified 4-aminopyrimidine analog 6, which showed a single-digit nanomolar and a micromolar potencies in p70S6K and Akt enzymatic assays. SAR optimization improved Akt enzymatic and p70S6K cellular potencies, reduced hERG liability, and ultimately discovered the promising candidate 37, which exhibited with a single digit nanomolar value in both p70S6K and Akt biochemical assays, and hERG activities (IC50 = 17.4 µM). This agent demonstrated dose-dependent efficacy in inhibiting mice breast cancer tumor growth and covered more than 90% pS6 inhibition up to 24 h at a dose of 200 mg/kg po.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Mammary Neoplasms, Animal/drug therapy , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Pyrimidines/pharmacology , Ribosomal Protein S6 Kinases, 70-kDa/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Area Under Curve , Dogs , Female , Half-Life , Haplorhini , Mice , Molecular Docking Simulation , Molecular Structure , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Pyrimidines/chemistry , Pyrimidines/pharmacokinetics , Rats , Ribosomal Protein S6 Kinases, 70-kDa/genetics , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Structure-Activity Relationship , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolismABSTRACT
Bis-aryl ureas have been disclosed previously as a potent class of Raf kinase inhibitors. Modifications in the amide portion led to an improvement in aqueous solubility, an important characteristic for an oral drug. Based on this finding, we hypothesize that this portion of the molecule is directed towards the solvent in Raf-1.
Subject(s)
Enzyme Inhibitors/pharmacology , MAP Kinase Kinase Kinase 1 , Proto-Oncogene Proteins c-raf/antagonists & inhibitors , Urea/analogs & derivatives , Urea/pharmacology , Amides/chemical synthesis , Amides/pharmacology , Baculoviridae/genetics , Enzyme Inhibitors/chemical synthesis , Humans , MAP Kinase Kinase Kinases/antagonists & inhibitors , Molecular Structure , Pyridines/chemistry , Pyridines/pharmacology , Recombinant Proteins/antagonists & inhibitors , Solubility , Structure-Activity Relationship , Urea/chemical synthesisABSTRACT
Inhibitors of the MAP kinase p38 provide a novel approach for the treatment of osteoporosis, inflammatory disorders, and cancer. We have identified N-(3-tert-butyl-1-methyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea as a potent and selective p38 kinase inhibitor in biochemical and cellular assays. This compound is orally active in two acute models of cytokine release (TNF-induced IL-6 and LPS-induced TNF) and a chronic model of arthritis (20-day murine collagen-induced arthritis).
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Urea/chemical synthesis , Urea/pharmacology , Administration, Oral , Animals , Arthritis/drug therapy , Cytokines/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Mice , Urea/analogs & derivatives , Urea/chemistry , Urea/therapeutic use , p38 Mitogen-Activated Protein KinasesABSTRACT
A series of crotyl ethers underwent intramolecular cyclizations in the presence of a novel catalytic couple, composed of tris(triphenylphosphine)rhodium(I) chloride and palladium(II) acetate, under Heck conditions initially described by Jeffery.(1) The data indicated that the combination of these two metal catalysts formed a synergistic interaction that mediated intramolecular couplings in a superior manner as compared to the use of palladium(II) acetate alone. When tris(triphenylphosphine)rhodium(I) chloride was added to the system, a distinct increase in rate and selectivity for the endocyclic form of the bicyclic ether products was generally observed. In addition, changing parameters such as dilution and intial pot temperature appeared to significantly affect rate and selectivity in the experiments involving the catalytic couple, but not as drastically with those that were done only in the presence of palladium(II) acetate. Substitution of bis(triphenylphosphine)palladium(II) acetate for palladium(II) acetate provided an outcome that slightly favored the endocyclic form of the bicyclic ether, but when tris(triphenylphosphine)rhodium(I) chloride was added as a cocatalyst, the ratio clearly favored the exocyclic isomer.
