ABSTRACT
Paediatric stroke constitute a medical and/or surgical emergency. The speed and timeliness of the treatment have a significant impact on the prognosis. The nursing role, from carrying out continuous observation to specific procedures, is essential in the assessment, the care pathway and the short-, medium- and long-term outcome for the child.
Subject(s)
Nurse's Role , Stroke/nursing , Child , Glasgow Coma Scale , Humans , Neuroscience Nursing , Pediatric NursingABSTRACT
The trifluoroethylamine group found in cathepsin K inhibitors like odanacatib can be replaced by a difluoroethylamine group. This change increased the basicity of the nitrogen which positively impacted the log D. This translated into an improved oral bioavailability in pre-clinical species. Difluoroethylamine compounds exhibit a similar potency against cathepsin K and selectivity profile against other cathepsins when compared to trifluoroethylamine analogs.
Subject(s)
Cathepsin K/antagonists & inhibitors , Ethylamines/chemistry , Protease Inhibitors/chemistry , Administration, Oral , Amides/chemistry , Animals , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Cathepsin K/metabolism , Dogs , Ethylamines/chemical synthesis , Ethylamines/pharmacokinetics , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , RatsABSTRACT
The discovery of the potent and selective prostaglandin D2 (PGD2) receptor (DP) antagonist [(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (13) is presented. Initial lead antagonists 6 and 7 were found to be potent and selective DP antagonists (DP Ki = 2.0 nM for each); however, they both suffered from poor pharmacokinetic profiles, short half-lives and high clearance rates in rats. Rat bile duct cannulation studies revealed that high concentrations of parent drug were present in the biliary fluid (Cmax = 1100 microM for 6 and 3900 microM for 7). This pharmacokinetic liability was circumvented by replacing the 7-methylsulfone substituent present in 6 and 7 with a fluorine atom resulting in antagonists with diminished propensity for biliary excretion and with superior pharmacokinetic profiles. Further optimization led to the discovery of the potent and selective DP antagonist 13.
Subject(s)
Indoles/chemical synthesis , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Airway Obstruction/drug therapy , Animals , Bile/metabolism , Binding, Competitive , Dogs , Hepatocytes/metabolism , Humans , In Vitro Techniques , Indoles/pharmacokinetics , Indoles/pharmacology , Macaca fascicularis , Male , Mice , Microsomes/metabolism , Nasal Decongestants/chemical synthesis , Nasal Decongestants/pharmacokinetics , Nasal Decongestants/pharmacology , Protein Binding , Rats , Rats, Sprague-Dawley , Sheep , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A novel indole series of PGD2 receptor (DP receptor) antagonists is presented. Optimization of this series led to the identification of potent and selective DP receptor antagonists. In particular, antagonists 35 and 36 were identified with Ki values of 2.6 and 1.8 nM, respectively. These two antagonists are also potent in a DP functional assay where they inhibit the PGD2 induced cAMP production in platelet rich plasma with IC50 values of 7.9 and 8.6 nM, respectively. The structure-activity relationships of this indole series of DP receptor antagonists will also be discussed.
Subject(s)
Indoles/chemistry , Indoles/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Indoles/chemical synthesis , Molecular Structure , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/metabolism , Safrole/analogs & derivatives , Safrole/chemistry , Structure-Activity RelationshipABSTRACT
The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4 (IC(50)<1nM) and also of LPS-induced TNF-alpha release in human whole blood (IC(50)<0.5microM). The same compounds are potent inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC(50)<0.1mg/kg ip) but require a dose of about 10mg/kg po in the squirrel monkey to produce an emetic response. From this series of compounds, 23a (L-454,560) was identified as an optimized compound.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Animals , Bronchoconstriction/drug effects , Cyclic Nucleotide Phosphodiesterases, Type 4 , Guinea Pigs , Humans , Inhibitory Concentration 50 , Phosphodiesterase Inhibitors/toxicity , Quinolines/toxicity , Rats , Saimiri , Sheep , Structure-Activity Relationship , Vomiting/chemically inducedABSTRACT
A series of novel ortho-substituted cinnamic acids have been synthesized, and their binding activity and selectivity on the four prostaglandin E(2) receptors evaluated. Many of them are very potent and selective EP(3) antagonists (K(i) 3-10 nM), while compound 9 is a very good and selective EP(2) agonist (K(i) 8 nM). The biological profile of the EP(2) agonist 9 in vivo and the metabolic profile of selected EP(3) antagonists are also reported.
Subject(s)
Cinnamates/chemical synthesis , Cinnamates/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Cell Line , Cinnamates/metabolism , Cyclic AMP/biosynthesis , Humans , Pharmacokinetics , Protein Binding , Receptors, Prostaglandin E, EP2 Subtype , Receptors, Prostaglandin E, EP3 Subtype , Structure-Activity RelationshipABSTRACT
A robust method for the solid phase synthesis of a series of selective caspase-3 peptide inhibitors is described. The inhibitors can be obtained after cleavage from the solid support without further purification.
Subject(s)
Caspase Inhibitors , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Caspase 3 , Cell Line , Cell Survival/drug effects , Combinatorial Chemistry Techniques , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50ABSTRACT
We have characterized some novel caged fluorescein diphosphates as photoactivatable, cell-permeable substrates for protein tyrosine phosphatases and explored their usefulness in identifying inhibitors of tyrosine phosphatases. 1-(2-Nitrophenyl)ethyl protected fluorescein diphosphate (NPE-FDP) undergoes rapid photolysis to release FDP upon irradiation with a 450-W UV immersion lamp and its by-product does not inactivate protein tyrosine phosphatase 1B (PTP1B) or alters the viability of cells. The generated FDP from photolysis of NPE-FDP was shown to have exactly the same properties as FDP, which can be used as a PTP substrate in pure enzyme assays. We have also demonstrated that the PTP activity can be measured using NPE-FDP in small droplets. Its advantage as an inert substrate before photolysis allows the possibility of applying nanospray technology in screening and optimizing PTP inhibitors through a large chemical library. Like other caged bioeffectors such as nucleotide and inositol trisphosphate, NPE-FDP is cell-permeable. The NPE-FDP can be photolyzed to generate FDP inside cells, and then can be hydrolyzed by phosphatases to produce fluorescein monophosphate and subsequently to fluorescein. Although Jurkat cells contain high concentrations of CD45, it has not been possible to use FDP as a substrate to measure CD45 activity in the intact cell. This is due to the hydrolysis of FDP by several other cellular phosphatases. However, NPE-FDP can be useful as a cell-permeable substrate for overexpressed phosphatases such as alkaline phosphatase.
