ABSTRACT
Leukotriene B(4) (LTB(4)) is a pro-inflammatory mediator that has been implicated in the pathogenesis of a number of diseases including inflammatory bowel disease (IBD) and psoriasis. Since the action of LTA(4) hydrolase is the rate-limiting step for LTB(4) production, this enzyme represents an attractive pharmacological target for the suppression of LTB(4) production. From an in-house screening program, SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) was identified as a potent inhibitor of LTA(4) hydrolase. Structure-activity relationship (SAR) studies around this structural class resulted in the identification of a number of novel, potent inhibitors of LTA(4) hydrolase, several of which demonstrated good oral activity in a mouse ex vivo whole blood assay.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Epoxide Hydrolases/antagonists & inhibitors , Pyrrolidines/chemical synthesis , Administration, Oral , Animals , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , In Vitro Techniques , Leukotriene B4/biosynthesis , Leukotriene B4/blood , Male , Mice , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Structure-Activity RelationshipABSTRACT
The FKBP12-rapamycin-associated protein (FRAP; also called RAFT1/mTOR) regulates translation initiation and entry into the cell cycle. Depriving cells of amino acids or treating them with the small molecule rapamycin inhibits FRAP and results in rapid dephosphorylation and inactivation of the translational regulators 4E-BP1(eukaryotic initiation factor 4E-binding protein 1) and p70(s6k) (the 70-kDa S6 kinase). Data published recently have led to the view that FRAP acts as a traditional mitogen-activated kinase, directly phosphorylating 4E-BP1 and p70(s6k) in response to mitogenic stimuli. We present evidence that FRAP controls 4E-BP1 and p70(s6k) phosphorylation indirectly by restraining a phosphatase. A calyculin A-sensitive phosphatase is required for the rapamycin- or amino acid deprivation-induced dephosphorylation of p70(s6k), and treatment of Jurkat I cells with rapamycin increases the activity of the protein phosphatase 2A (PP2A) toward 4E-BP1. PP2A is shown to associate with p70(s6k) but not with a mutated p70(s6k) that is resistant to rapamycin- and amino acid deprivation-mediated dephosphorylation. FRAP also is shown to phosphorylate PP2A in vitro, consistent with a model in which phosphorylation of PP2A by FRAP prevents the dephosphorylation of 4E-BP1 and p70(s6k), whereas amino acid deprivation or rapamycin treatment inhibits FRAP's ability to restrain the phosphatase.
Subject(s)
Carrier Proteins/antagonists & inhibitors , Immunophilins/antagonists & inhibitors , Oxazoles/pharmacology , Phosphoprotein Phosphatases/metabolism , Phosphotransferases (Alcohol Group Acceptor) , Ribosomal Protein S6 Kinases/metabolism , Sirolimus/pharmacology , Enzyme Inhibitors/pharmacology , Glutathione Transferase/metabolism , Humans , Jurkat Cells , Kinetics , Marine Toxins , Models, Biological , Phosphorylation , Protein Phosphatase 2 , Recombinant Fusion Proteins/metabolism , TOR Serine-Threonine Kinases , Tacrolimus Binding Proteins , TransfectionABSTRACT
Analogues of the dibasic antiarrhythmic agent disobutamide (2) were prepared and evaluated for antiarrhythmic efficacy, myocardial depression, and anticholinergic activity. The replacement of an isopropyl group in disobutamide by an acetyl group led to the monobasic analogue SC-40230, 7a, which demonstrated good antiarrhythmic activity accompanied by less myocardial depressant and anticholinergic activities. In addition, it did not induce clear cytoplasmic vacuoles as did the parent compound. SC-40230 was chosen from among other analogues as a candidate for clinical evaluation. Other compounds prepared and evaluated included indolizidinones and a secondary amine isomer of disobutamide.
Subject(s)
Anti-Arrhythmia Agents/chemical synthesis , Piperidines , Animals , Anti-Arrhythmia Agents/metabolism , Anti-Arrhythmia Agents/pharmacology , Binding Sites , Dogs , Drug Evaluation , Hydrogen-Ion Concentration , Isomerism , Rats , Receptors, Muscarinic/metabolism , Sodium Channels/drug effects , Structure-Activity RelationshipABSTRACT
A series of 22-hydroxycholesterol derivatives with a modified side chain terminus was prepared. These agents were evaluated in vitro and in vivo for their ability to suppress HMG CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis. In tissue culture assays, 22-hydroxycholesterol as well as the side chain modified analogues were potent inhibitors of HMG CoA reductase. However, only those sterols with a modified side chain terminus were effective suppressors of liver reductase when administered ig to rats. 22-Hydroxy-25-methylcholesterol (4a) and 25-fluoro-22-hydroxycholesterol (15a) significantly lowered serum cholesterol levels when administered ig to primates; 25-chloro-22-hydroxycholesterol (15b) and the analogue with a cyclopropyl terminus, 20b, were ineffective. The cholesterol-lowering sterols did not significantly alter lipoprotein levels; however, the two compounds have been shown to inhibit acyl-coenzyme A:cholesterol acyl-transferase (ACAT) in tissue culture studies.
Subject(s)
Cholesterol/blood , Hydroxycholesterols/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Animals , Fibroblasts/enzymology , Humans , Lipoproteins/blood , Macaca mulatta , Male , RatsABSTRACT
A survey was conducted in an urban Indian community to investigate the prevalence and epidemiology of health problems in children from birth up to 8 years of age. The prevalences of priority health problems in this age group were as follows: dental caries (90%), undernutrition (68,8%), failure to obtain measles immunization (57,2%) and skin infestations (14,9%). The significant epidemiological parameters investigated included family size, per capita family income, immunization and nutritional status. The influence of these factors upon health problems is considered. The availability and utilization of comprehensive health services were investigated. Problems associated with health screening as a method of determining health problems are discussed.
Subject(s)
Health Status , Health , Urban Health , Child , Child, Preschool , Dental Caries/epidemiology , Family , Female , Health Services , Health Surveys , Humans , Immunization , Income , India/ethnology , Infant , Infant, Newborn , Male , Measles/prevention & control , Morbidity , Nutrition Disorders/epidemiology , Nutritional Physiological Phenomena , Pregnancy , Skin Diseases/epidemiology , South AfricaABSTRACT
A series of oxopyridobenzothiazines (azaphenothiazines) were prepared and evaluated for binding to the benzodiazepine receptor, anticonvulsant activity in the pentylenetetrazole-induced convulsion assay, and, in two cases, ability to increase punished responding in a standard conflict test. While parent compound 1a showed binding affinity comparable to chlorodiazepoxide (CDP), its potency in the anticonvulsant assay and the anticonflict test was considerably weaker than CDP. Of the variety of derivatives synthesized, only the 7-chloro compound 1b showed receptor affinity comparable to 1a with slightly improved in vivo activity. The poor correlation between receptor binding and in vivo activity may be due to variability in absorption or pharmacological responses unrelated to affinity for the benzodiazepine receptor.
Subject(s)
Anticonvulsants , Pyridines/chemical synthesis , Receptors, Cell Surface/metabolism , Thiazines/chemical synthesis , Animals , Conflict, Psychological , Drinking Behavior/drug effects , Male , Mice , Pyridines/metabolism , Receptors, GABA-A , Thiazines/metabolismABSTRACT
A series of spirolactones containing a cyclopropane ring in the molecule was examined for its effects on the mineralocorticoid receptor. The results were compared with those of a similar series of spirolactones in which the cyclopropane ring was replaced by a double bond. Insertion of a double bond or an alpha-cyclopropane ring into the 1,2 or the 6,7 position leads to a reduction in the binding affinity. The pi-bonding system of the beta-cyclopropane ring at C-6 and C-7 does not promote binding to the receptor. The presence of the 6 beta, 7 beta-cyclopropane ring may deter metabolic activation to account for the enhanced in vivo activity.
Subject(s)
Mineralocorticoids/antagonists & inhibitors , Spironolactone/analogs & derivatives , Chemical Phenomena , Chemistry , Mineralocorticoid Receptor Antagonists , Molecular Conformation , Receptors, Mineralocorticoid , Receptors, Steroid/metabolism , Spironolactone/pharmacology , Structure-Activity RelationshipABSTRACT
15-Ketoprogesterone is as active as spironolactone in blocking the mineralocorticoid effect of deoxycorticosterone acetate. This activity is reduced when a methylene group is attached to the 6beta, 7beta position. The title compound was prepared from 15alpha-acetoxy-6-dehydroprogesterone. Methylenation of the delta6 double bond with dimethyloxosulfonium methylide proceeds steroselectively from the beta side of the molecule.
