ABSTRACT
A series of N6,2-disubstituted adenosine analogues have been synthesized and their functional activity measured against A2a and A1 receptors. Examples of compounds with both a lipophilic N6-substituent and amino-functionalized 2-position were highly active at the A2a receptor on the human neutrophil.
Subject(s)
Adenosine/chemistry , Adenosine/pharmacology , Purinergic P1 Receptor Agonists , Adenosine/analogs & derivatives , Anti-Inflammatory Agents/chemistry , GTP-Binding Proteins , Solubility , Structure-Activity RelationshipABSTRACT
Analogues of 4-Guanidino-Neu5Ac2en (Zanamivir) have been prepared containing carbamate substituents at the 7-hydroxy position. (4S,5R,6R)-5-Acetylamino-6-[1R-[(6-aminohexyl)carbamoyloxy]-2R,3-dihydroxypropyl]-4-guanidino-5,6-dihydro-4H-pyran-2carboxylic acid and (4S,5R,6R)-5-Acetylamino-6-[1R-[heptylcarbamoyloxy]-2R,3-dihydroxypropyl]-4-guanidino-5,6-dihydro4H-pyran2-carboxylic acid were the two analogues possessing activity comparable to Zanamivir, showing potent inhibition of influenza virus sialidases and good antiviral activity in vitro.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Influenza A virus/enzymology , Influenza B virus/enzymology , Neuraminidase/antagonists & inhibitors , Sialic Acids/chemical synthesis , Sialic Acids/pharmacology , Crystallography, X-Ray , Glycerol/chemistry , Guanidines , Humans , Influenza A virus/drug effects , Influenza B virus/drug effects , Pyrans , Viral Plaque Assay , ZanamivirABSTRACT
4-Amino- and 4-guanidino-4H-pyran-6-carboxamides 4 and 5 related to zanamivir (GG167) are a new class of inhibitors of influenza virus sialidases. Structure--activity studies reveal that, in general, secondary amides are weak inhibitors of both influenza A and B viral sialidases. However, tertiary amides, which contain one or more small alkyl groups, show much greater inhibitory activity, particularly against the influenza A virus enzyme. The sialidase inhibitory activities of these compounds correlate well with their in vitro antiviral efficacy, and several of the most potent analogues displayed useful antiviral activity in vivo when evaluated in a mouse model of influenza A virus infection. Carboxamides which were highly active sialidase inhibitors in vitro also showed good antiviral activity in the mouse efficacy model of influenza A infection when administered intranasally but displayed modest activity when delivered by the intraperitoneal route.
Subject(s)
Antiviral Agents/pharmacology , Enzyme Inhibitors/pharmacology , Guanidines/pharmacology , Influenza A virus/drug effects , Influenza B virus/drug effects , Neuraminidase/antagonists & inhibitors , Pyrans/pharmacology , Sialic Acids/pharmacology , Administration, Intranasal , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Guanidines/chemical synthesis , Guanidines/chemistry , Guanidines/pharmacokinetics , Influenza A virus/enzymology , Influenza B virus/enzymology , Injections, Intraperitoneal , Mice , Orthomyxoviridae Infections/drug therapy , Orthomyxoviridae Infections/enzymology , Pyrans/chemical synthesis , Pyrans/chemistry , Pyrans/pharmacokinetics , Sialic Acids/chemistry , Sialic Acids/pharmacokinetics , Structure-Activity Relationship , ZanamivirABSTRACT
The first paper in this series (see previous article) described structure-activity studies of carboxamide analogues of zanamivir binding to influenza virus sialidase types A and B and showed that inhibitory activity of these compounds was much greater against influenza A enzyme. To understand the large differences in affinities, a number of protein-ligand complexes have been investigated using crystallography and molecular dynamics. The crystallographic studies show that the binding of ligands containing tertiary amide groups is accompanied by the formation of an intramolecular planar salt bridge between two amino acid residues in the active site of the enzyme. It is proposed that the unexpected strong binding of these inhibitors is a result of the burial of hydrophobic surface area and salt-bridge formation in an environment of low dielectric. In sialidase from type A virus, binding of the carboxamide moeity and salt-bridge formation have only a minor effect on the positions of the surrounding residues, whereas in type B enzyme, significant distortion of the protein is observed. The results suggest that the decreased affinity in enzyme from influenza B is directly correlated with the small changes that occur in the amino acid residue interactions accompanying ligand binding. Molecular dynamics calculations have shown that the tendency for salt-bridge formation is greater in influenza A sialidase than influenza B sialidase and that this tendency is a useful descriptor for the prediction of inhibitor potency.
Subject(s)
Acetamides/chemistry , Antiviral Agents/chemistry , Enzyme Inhibitors/chemistry , Influenza A virus/enzymology , Influenza B virus/enzymology , Neuraminidase/chemistry , Pyrans/chemistry , Sialic Acids/chemistry , Acetamides/metabolism , Acetamides/pharmacology , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Binding Sites , Crystallography, X-Ray , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Guanidines , Models, Molecular , Neuraminidase/antagonists & inhibitors , Neuraminidase/metabolism , Protein Conformation , Pyrans/metabolism , Pyrans/pharmacology , Sialic Acids/metabolism , Sialic Acids/pharmacology , ZanamivirABSTRACT
A novel series of tetrahydrobenzodioxinopyrroles has been identified as potent and selective alpha 2-adrenoceptor antagonists. Convergent syntheses have been developed that allowed the preparation of analogues and their enantiomers. A compound of particular interest is the 5-fluoro substituted analogue (fluparoxan).
Subject(s)
Adrenergic alpha-2 Receptor Antagonists , Adrenergic alpha-Antagonists/chemical synthesis , Adrenergic alpha-Antagonists/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Adrenergic alpha-Antagonists/chemistry , Animals , In Vitro Techniques , Male , Mice , Molecular Structure , Piperoxan/analogs & derivatives , Piperoxan/chemical synthesis , Piperoxan/chemistry , Piperoxan/pharmacology , Pyrroles/chemistry , Rats , StereoisomerismABSTRACT
In this paper, the heating (temperature) distribution patterns of an array of uniformly and step-insulated interstitial antennas located in inhomogeneous tissue and cancerous regions of the human body are calculated. Specifically, the bioheat equation, which takes into account various heat exchange mechanisms such as blood flow rate, heat conduction, and metabolic heat generation, was solved using the finite difference method, while the electromagnetic power absorbed (SAR) in the tissue region heated using an array of interstitial antennas was determined using the finite-difference time-domain (FDTD) method. Numerical results showing the validation of the developed computer program are presented, and the effect of varying parameters such as the blood flow rate on the resulting heating rate and patterns are examined. Possible clinical implementation of the developed temperature distribution-EM power deposition pattern computer code in treatment planning is described.
Subject(s)
Heating , Hyperthermia, Induced/instrumentation , Microwaves/therapeutic use , Absorption , Blood Flow Velocity , Body Temperature Regulation , Computer Simulation , Equipment Design , Humans , Models, Biological , TemperatureABSTRACT
The effects on plasma renin activity (PRA), mean arterial blood pressure (MABP) and heart rate (HR) of GR70982, a low molecular weight inhibitor of human renin, were studied in conscious marmosets. In vitro, GR70982 is a potent and selective inhibitor of human plasma renin (concentration producing 50% inhibition (IC50): human renin = 6.9 x 10(-9) M; porcine pepsin and bovine cathepin D = greater than 10(-3) M). In normotensive marmosets, i.v. GR70982 (0.001-0.1 mg kg-1) produced a dose-related inhibition of PRA. Larger oral doses (0.2, 1 and 5 mg kg-1) were required to achieve similar effects. In renin-dependent hypertensive marmosets, i.v. GR70982 (0.01 and 0.5 mg kg-1) produced dose-related decreases in MABP (-12 and -18 mm Hg) and PRA (-93 and -100%), with only minimal effects on HR. A 7-day continuous i.v. infusion of GR70982 (0.36 mg kg-1 day-1) in sodium-deplete marmosets produced a gradual decrease in MABP (-17 mm Hg at day 7, cf. control), accompanied by an inhibition of PRA (approximately 75%) and minimal HR effects.
