ABSTRACT
Diphenylphosphinic amides and diphenylphosphine oxides have been synthesized and tested as inhibitors of the Kv1.5 potassium ion channel as a possible treatment for atrial fibrillation. In vitro structure-activity relationships are discussed and several compounds with Kv1.5 IC(50) values of <0.5 µM were discovered. Selectivity over the ventricular IKs current was monitored and selective compounds were found. Results from a rabbit PD-model are included.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Kv1.5 Potassium Channel/antagonists & inhibitors , Oxides/chemical synthesis , Oxides/pharmacology , Phosphines/chemical synthesis , Phosphines/pharmacology , Amides/chemistry , Animals , Biphenyl Compounds/chemistry , Humans , Inhibitory Concentration 50 , Molecular Structure , Oxides/chemistry , Phosphines/chemistry , Phosphinic Acids/chemistry , Protein Binding/drug effects , Rabbits , Structure-Activity RelationshipABSTRACT
Epidemic keratoconjunctivitis (EKC) is a severe disease of the eye, caused by members of the Adenoviridae (Ad) family, with symptoms such as keratitis, conjunctivitis, pain, edema, and reduced vision that may last for months or years. There are no vaccines or antiviral drugs available to prevent or treat EKC. It was found previously that EKC-causing Ads use sialic acid as a cellular receptor and demonstrated that soluble, sialic acid-containing molecules can prevent infection. In this study, multivalent sialic acid constructs based on 10,12-pentacosadiynoic acid (PDA) have been synthesized, and these constructs are shown to be efficient inhibitors of Ad binding (IC(50) = 0.9 µM) and Ad infectivity (IC(50) = 0.7 µM). The mechanism of action is to aggregate virus particles and thereby prevent them from binding to ocular cells. Such formulations may be used for topical treatment of adenovirus-caused EKC.
Subject(s)
Adenoviridae/drug effects , Adenovirus Infections, Human/drug therapy , Alkynes/chemical synthesis , Antiviral Agents/chemical synthesis , Keratoconjunctivitis/drug therapy , Sialic Acids/chemical synthesis , Alkynes/chemistry , Alkynes/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cells, Cultured , Cornea/cytology , Epidemics , Epithelial Cells/cytology , Epithelial Cells/drug effects , Epithelial Cells/virology , Humans , Keratoconjunctivitis/virology , Liposomes , Polyethylene Glycols/chemical synthesis , Polyethylene Glycols/chemistry , Polyethylene Glycols/pharmacology , Sialic Acids/chemistry , Sialic Acids/pharmacology , Structure-Activity Relationship , Virion/drug effectsABSTRACT
Described is the synthesis of a fluorescent LacNAc derivative appended with a 3'-deoxy-3'-naphthamido functionality, 2-(fluorescein-5/6-amido)ethyl 3-deoxy-3-(2-naphthamido)-beta-D-galactopyranosyl-(1-->4)-2-acetamido-2-deoxy-beta-D-glucopyranoside, which confers high affinity (Kd 170 nM) and selectivity for galectin-3 via a stacking interaction with Arg144. Its use as a selective and sensitive galectin-3 probe is demonstrated with fluorescence polarization measurements.
