ABSTRACT
Inhibition of phosphoinositide 3-kinase (PI3K) signaling through PI3Kα has received significant attention for its potential in cancer therapy. While the PI3K pathway is a well-established and widely pursued target for the treatment of many cancer types due to the high frequency of abnormal PI3K signaling, glioblastoma multiforme (GBM) is particularly relevant because the pathway is implicated in more than 80% of GBM cases. Herein, we report the identification of PI3K inhibitors designed to cross the blood-brain barrier (BBB) to engage their target where GBM tumors reside. We leveraged our historical experience with PI3K inhibitors to identify correlations between physicochemical properties and transporter efflux as well as metabolic stability to focus the selection of molecules for further study.
Subject(s)
Blood-Brain Barrier/metabolism , Drug Design , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Dogs , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Female , Humans , Hydrogen Bonding , Madin Darby Canine Kidney Cells , Mice , Permeability , Surface PropertiesABSTRACT
A general method for the synthesis of 1,3,5-trisubstituted 1,2,4-triazoles has been developed from reaction of carboxylic acids, primary amidines, and monosubstituted hydrazines. This highly regioselective and one-pot process provides rapid access to highly diverse triazoles.
Subject(s)
Amidines/chemistry , Carboxylic Acids/chemistry , Hydrazines/chemistry , Hydrazines/chemical synthesis , Triazoles/chemical synthesis , Catalysis , Combinatorial Chemistry Techniques , Molecular StructureABSTRACT
Further investigations towards novel glycopeptide/beta-lactam heterodimers are reported. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons, 4, 2, 5 and 10, 18, 25 respectively, were chemically linked to yield heterodimer antibiotics. These novel compounds were designed to inhibit Gram-positive bacterial cell wall biosynthesis by simultaneously targeting the principal cellular targets of both glycopeptides and beta-lactams. The positional attachment of both the vancomycin and the cephalosporin central cores has been explored and the SAR is reported. This novel class of bifunctional antibiotics 28-36 all displayed remarkable potency against a wide range of Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). A subset of compounds, 29, 31 and 35 demonstrated excellent bactericidal activity against MRSA (ATCC 33591) and 31 and 35 also exhibited superb in vivo efficacy in a mouse model of MRSA infection. As a result of this work compound 35 was selected as a clinical candidate, TD-1792.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Cephalosporins/chemical synthesis , Cephalosporins/pharmacology , Drug Discovery/methods , Glycopeptides/chemical synthesis , Glycopeptides/pharmacology , beta-Lactams/chemical synthesis , beta-Lactams/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Cephalosporins/chemistry , Dimerization , Drug Design , Female , Glycopeptides/chemistry , Gram-Positive Bacteria/drug effects , Magnetic Resonance Spectroscopy , Methicillin-Resistant Staphylococcus aureus/drug effects , Mice , Microbial Sensitivity Tests , Molecular Structure , beta-Lactams/chemistryABSTRACT
Novel derivatives of N-decylaminoethylvancomycin (2), containing appended hydrophilic groups were synthesized and their antibacterial activity and ADME properties were evaluated. The compounds were prepared by reacting amines with the C-terminus (C-) of 2 using PyBOP mediated amide formation, or with the resorcinol-like (R-) position of 2 using a Mannich aminomethylation reaction. These analogs retained the antibacterial activity of 2 against methicillin-resistant staphylococci and vancomycin-resistant enterococci. Compounds with a negatively charged auxiliary group also exhibited improved ADME properties relative to 2. In particular, R-phosphonomethylaminomethyl derivative 21 displayed good in vitro antibacterial activity, high urinary recovery and low distribution to liver and kidney tissues. Based on these results, 21 was advanced into development as TD-6424, and is currently in human clinical trials. The generic name telavancin has recently been approved for compound 21.
