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1.
J Nephrol ; 32(6): 1021-1031, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31617158

ABSTRACT

BACKGROUND: Peritoneal dialysis (PD) is an optimal renal replacement therapy for patients while waiting for kidney transplantation, but functional failure of the peritoneal membrane (PM), mainly induced by exposure to PD solutions, force many patients to early abandon PD therapy. PM function is evaluated by the peritoneal equilibration test (PET), a tedious technique only detecting alterations in extensively damaged PM. In a previous study, we showed that peritoneal dialysis effluent contained extracellular vesicles (PDE-EV), and that their proteome was significantly different between newly enrolled and long-term PD patients. Here, we report the results of a longitudinal study and compare PDE-EV proteome changes with PET results. METHODS: PDE was collected from 11 patients every 6 months (coincident with PET controls) from 0 months up to 24 months on PD. PDE-EV were isolated by size-exclusion chromatography and the proteome was analyzed by mass spectrometry (LC-MS/MS). Bioinformatic analyses were conducted to evaluate differences between groups. RESULTS: At follow-up endpoint, patients were classified as Stable (n = 7) or Unstable (n = 4) according to PET evolution. Strikingly, PDE-EV from the Stable group showed a significantly higher protein expression compared to Unstable patients already at 6 months on PD, when PET alterations had not been detected yet. CONCLUSIONS: PDE-EV proteome show alterations much earlier than PET monitoring, thus unveiling the potential of PDE-EV proteins as feasible biomarkers of PM alteration in PD patients.


Subject(s)
Dialysis Solutions/pharmacokinetics , Extracellular Vesicles/metabolism , Kidney Failure, Chronic/therapy , Peritoneal Dialysis/methods , Proteomics/methods , Aged , Aged, 80 and over , Biomarkers/metabolism , Chromatography, Liquid , Female , Follow-Up Studies , Gene Expression Profiling , Humans , Kidney Failure, Chronic/metabolism , Male , Middle Aged , Peritoneum/metabolism , Tandem Mass Spectrometry , Time Factors
2.
PLoS One ; 12(5): e0176987, 2017.
Article in English | MEDLINE | ID: mdl-28489901

ABSTRACT

Peritoneal Dialysis (PD) is considered the best option for a cost-effective mid-term dialysis in patients with Chronic Renal Failure. However, functional failure of the peritoneal membrane (PM) force many patients to stop PD treatment and start haemodialysis. Currently, PM functionality is monitored by the peritoneal equilibration test, a tedious technique that often show changes when the membrane damage is advanced. As in other pathologies, the identification and characterization of extracellular vesicles (EVs) in the peritoneal dialysis efflux (PDE) may represent a non-invasive alternative to identify biomarkers of membrane failure. Using size-exclusion chromatography, we isolated EVs from PDE in a group of patients. Vesicles were characterized by the presence of tetraspanin markers, nanoparticle tracking analysis profile, cryo-electron microscopy and mass spectrometry. Here, we report the isolation and characterization of PDE-EVs. Based on mass spectrometry, we have found a set of well-conserved proteins among patients. Interestingly, the peptide profile also revealed remarkable changes between newly enrolled and longer-treated PD patients. These results are the first step to the identification of PDE-EVs based new markers of PM damage, which could support clinicians in their decision-making in a non-invasive manner.


Subject(s)
Extracellular Vesicles/pathology , Peritoneal Dialysis , Peritoneum/pathology , Proteome/analysis , Proteomics , Adult , Aged , Biomarkers/analysis , Biomarkers/metabolism , Extracellular Vesicles/metabolism , Female , Humans , Male , Middle Aged , Peritoneal Dialysis/methods , Peritoneum/metabolism , Proteome/metabolism , Proteomics/methods
3.
Eur J Med Chem ; 113: 102-33, 2016 May 04.
Article in English | MEDLINE | ID: mdl-26922232

ABSTRACT

Monocyclic and bicyclic ring systems were investigated as the "core" section of a series of diphenylsulphone-containing acetic acid CRTh2 receptor antagonists. A range of potencies were observed and single-digit nanomolar potencies were obtained in both the monocyclic and bicyclic cores. Residence times for the monocyclic compounds were very short. Some of the bicyclic cores displayed better residence times. A methyl group in the northern part of the core, between the head and tail was a necessary requirement for the beginnings of long residence times. Variations of the tail substitution maximised potencies and residence times.


Subject(s)
Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Sulfones/chemistry , Sulfones/pharmacology , Dose-Response Relationship, Drug , Humans , Kinetics , Molecular Structure , Structure-Activity Relationship , Sulfones/chemical synthesis
4.
Bioorg Med Chem Lett ; 25(6): 1217-22, 2015 Mar 15.
Article in English | MEDLINE | ID: mdl-25690784

ABSTRACT

Synthesis and SAR of a series of 7-azaindoles as Orai channel inhibitors showing good potency inhibiting IL-2 production in Jurkat cells is described. Compound 14d displaying best pharmacokinetic properties was further characterized in a model of allergen induced asthma showing inhibition in the number of eosinophils in BALF. High lipophilicity remains as one of the main challenges for this class of compounds.


Subject(s)
Calcium Channel Blockers/chemistry , Calcium Channels/chemistry , Indoles/chemistry , Pyridines/chemistry , Pyrroles/chemistry , Animals , Asthma , Aza Compounds/chemistry , Calcium Channel Blockers/pharmacokinetics , Calcium Channel Blockers/therapeutic use , Calcium Channels/metabolism , Disease Models, Animal , Drug Evaluation, Preclinical , Half-Life , Humans , Hypersensitivity/drug therapy , Hypersensitivity/immunology , Indoles/pharmacokinetics , Indoles/therapeutic use , Interleukin-2/blood , Interleukin-2/metabolism , Jurkat Cells , Microsomes/metabolism , Models, Biological , Ovalbumin/immunology , Protein Binding , Pyridines/pharmacokinetics , Pyridines/therapeutic use , Pyrroles/pharmacokinetics , Pyrroles/therapeutic use , Rats , Structure-Activity Relationship
6.
Bioorg Med Chem Lett ; 24(21): 5123-6, 2014 Nov 01.
Article in English | MEDLINE | ID: mdl-25437505

ABSTRACT

Extensive structure-activity relationship (SAR) and structure-kinetic relationship (SKR) studies in the bicyclic heteroaromatic series of CRTh2 antagonists led to the identification of several molecules that possessed both excellent binding and cellular potencies along with long receptor residence times. A small substituent in the bicyclic core provided an order of magnitude jump in dissociation half-lives. Selected optimized compounds demonstrated suitable pharmacokinetic profiles.


Subject(s)
Acetates/chemistry , Bridged Bicyclo Compounds/chemistry , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemical synthesis , Acetates/pharmacokinetics , Animals , Half-Life , Humans , Indoles/chemistry , Injections, Intravenous , Rats , Rats, Wistar , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/metabolism , Structure-Activity Relationship
9.
Anesthesiology ; 117(6): 1223-33, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23135259

ABSTRACT

BACKGROUND: It has been suggested that predicting difficult tracheal intubation is useless because of the poor predictive capacity of individual signs and scores. The authors tested the hypothesis that an accurate prediction of difficult tracheal intubation using simple clinical signs is possible using a computer-assist model. METHODS: In a cohort of 1,655 patients, the authors analyzed the predictive properties of each of the main signs (Mallampati score, mouth opening, thyromental distance, and body mass index) to predict difficult tracheal intubation. They built the best score possible using a simple logistic model (SCOREClinic) and compared it with the more recently described score in the literature (SCORENaguib). Then they used a boosted tree analysis to build the best score possible using computer-assisted calculation (SCOREComputer). RESULTS: Difficult tracheal intubation occurred in 101 patients (6.1%). The predictive properties of each sign remain low (maximum area under the receiver operating characteristic curve 0.70). Using receiver operating characteristic curve, the global prediction of the SCOREClinic (0.74, 95% CI: 0.72-0.76) was greater than that of the SCORENaguib (0.66, 95% CI: 0.60-0.72, P<0.001) but significantly lower than that of the SCOREComputer (0.86, 95% CI: 0.84-0.91, P<0.001). The proportion of patients in the inconclusive zone was 71% using SCORENaguib, 56% using SCOREClinic, and only 32 % using SCOREComputer (all P<0.001). CONCLUSION: Computer-assisted models using complex interaction between variables enable an accurate prediction of difficult tracheal intubation with a low proportion of patients in the inconclusive zone. An external validation of the model is now required.


Subject(s)
Body Mass Index , Decision Making, Computer-Assisted , Intubation, Intratracheal/adverse effects , Intubation, Intratracheal/trends , Adolescent , Adult , Aged , Female , Humans , Intubation, Intratracheal/methods , Male , Middle Aged , Predictive Value of Tests , Time Factors , Young Adult
10.
Bioorg Med Chem Lett ; 22(10): 3431-6, 2012 May 15.
Article in English | MEDLINE | ID: mdl-22521646

ABSTRACT

A new class of p38α inhibitors based on a biaryl-triazolopyridine scaffold was investigated. X-ray crystallographic data of the initial lead compound cocrystallised with p38α was crucial in order to uncover a unique binding mode of the inhibitor to the hinge region via a pair of water molecules. Synthesis and SAR was directed towards the improvement of binding affinity, as well as ADME properties for this new class of p38α inhibitors and ultimately afforded compounds showing good in vivo efficacy.


Subject(s)
Benzamides/pharmacology , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Crystallography, X-Ray , Models, Molecular , Structure-Activity Relationship
11.
Bioorg Med Chem Lett ; 22(8): 2784-8, 2012 Apr 15.
Article in English | MEDLINE | ID: mdl-22425453

ABSTRACT

A series of aminopyrazines as inhibitors of Syk kinase activity and showing inhibition of LAD2 cells degranulation is described. Optimization of the carboxamide motif with aminomethylpiperidines provided high potency inhibiting Syk but low cellular activity. Amides of cis and trans adamantanol showed good inhibitory activity against Syk as well as remarkable activity in LAD2 cells degranulation assay.


Subject(s)
Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazines/chemical synthesis , Pyrazines/pharmacology , Adamantane/analogs & derivatives , Adamantane/chemistry , Adamantane/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Structure , Pyrazines/chemistry , Syk Kinase
12.
ACS Med Chem Lett ; 2(3): 213-8, 2011 Mar 10.
Article in English | MEDLINE | ID: mdl-24900298

ABSTRACT

The structure-activity relationships for a series of pyrazine-based A2B adenosine receptor antagonists are described. From this work, LAS101057 (17), a potent, selective, and orally efficacious A2B receptor antagonist, was identified as a clinical development candidate. LAS101057 inhibits agonist-induced IL-6 production in human fibroblasts and is active in an ovalbumin (OVA)-sensitized mouse model after oral administration, reducing airway hyperresponsiveness to methacholine, Th2 cytokine production, and OVA-specific IgE levels.

13.
J Med Chem ; 52(17): 5531-45, 2009 Sep 10.
Article in English | MEDLINE | ID: mdl-19678708

ABSTRACT

A novel series of aminopyridine N-oxides were designed, synthesized, and tested for their ability to inhibit p38alpha MAP kinase. Some of these compounds showed a significant reduction in the LPS-induced TNFalpha production in human whole blood. Structure-activity relationship studies revealed that N-oxide oxygen was essential for activity and was probably a determinant factor for a marked selectivity against other related kinases. Compound 45 was identified as a potent and selective p38alpha inhibitor with an appropriate balance between potency and pharmacokinetics. In vivo efficacy of 45 was demonstrated in reducing TNFalpha levels in an acute murine model of inflammation (ED(50) = 1 mg/kg in LPS-induced TNFalpha production when dosed orally 1.5 h prior to LPS administration). The oral efficacy of 45 was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally (ED(50) = 4.5 mg/kg).


Subject(s)
Aminopyridines/chemistry , Aminopyridines/pharmacology , Drug Design , Oxides/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Aminopyridines/chemical synthesis , Aminopyridines/therapeutic use , Animals , Arthritis, Experimental/blood , Arthritis, Experimental/drug therapy , Catalytic Domain , Cell Line , Humans , Inhibitory Concentration 50 , Male , Models, Molecular , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/therapeutic use , Rats , Rats, Wistar , Structure-Activity Relationship , Substrate Specificity , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/blood , p38 Mitogen-Activated Protein Kinases/chemistry
14.
Bioorg Med Chem ; 17(10): 3618-29, 2009 May 15.
Article in English | MEDLINE | ID: mdl-19398343

ABSTRACT

A number of 1,3-dialkyl-9-deazaxanthines (9-dAXs), bearing a variety of N-substituted benzyloxycarbonylamino substituents at position 8, were prepared and evaluated for their binding affinity to the recombinant human adenosine receptors (hARs), chiefly to the hA(2B) and hA(2A) AR subtypes. Several ligands endowed with excellent binding affinity to the hA(2B) receptors, but low selectivity versus hA(2A) and hA(1) were identified. Among these, 1,3-dimethyl-N-3'-thienyl carbamate 15 resulted as the most potent ligand at hA(2B) (K(i)=0.8 nM), with a low selectivity versus hA(2A) (hA(2A)/hA(2B)=12.6) and hA(1) (hA(1)/hA(2B)=12.5) and a higher selectivity versus hA(3) (hA(3)/hA(2B)=454). When tested in functional assays in vitro, compound 15 exhibited high antagonist activities and efficacies versus both the A(2A) and A(2B) receptor subtypes, with pA(2) values close to the corresponding pK(i)s. A comparative analysis of structure-affinity and structure-selectivity relationships of the similar analogues 8-N-substituted benzyloxycarbonylamino- and 8-N-substituted phenoxyacetamido-9-dAXs suggested that their binding modes at the hA(2B) and hA(2A) ARs may strongly differ. Computational studies help to clarify this striking difference arising from a simple, albeit crucial, structural change, from CH(2)OCON to OCH(2)CON, in the para-position of the 8-phenyl ring.


Subject(s)
Carbamates/chemistry , Purinergic P1 Receptor Antagonists , Xanthines/chemistry , Adenosine A1 Receptor Antagonists , Adenosine A2 Receptor Antagonists , Adenosine A3 Receptor Antagonists , Animals , Carbamates/chemical synthesis , Carbamates/pharmacology , Cell Line , Drug Design , Humans , Male , Models, Chemical , Rats , Rats, Wistar , Receptor, Adenosine A1/metabolism , Receptor, Adenosine A2A/metabolism , Receptor, Adenosine A2B/metabolism , Receptor, Adenosine A3/metabolism , Receptors, Purinergic P1/metabolism , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Xanthines/chemical synthesis , Xanthines/pharmacology
15.
Crit Care Med ; 36(10): 2740-5, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18766095

ABSTRACT

BACKGROUND: As a result of donor heart shortage, resorting to marginal heart donors is being promoted. Dobutamine is usually used to support these potential donors and has been proposed to identify the reversible part of the brain death-induced myocardial dysfunction before potential organ donation. But dobutamine impairs the oxygen supply-demand balance and may increase myocardial ischemia. The aim of this study was to compare the effects of dobutamine and glucose-insulin-potassium on the left ventricular systolic dysfunction in brain dead patients. METHODS AND RESULTS: One hundred thirty-five consecutive brain dead patients were prospectively screened. Twelve of them with severe acute heart failure defined by an echocardiographic ejection fraction area <30% received 10 microg/kg/min dobutamine infusion over 30 min and, after return to baseline cardiac function, glucose-insulin-potassium infusion over 120 min. With dobutamine, ejection fraction area significantly increased (39 +/- 14 vs. 21 +/- 6%, p < 0.0001) whereas mean diastolic arterial pressure decreased (71 +/- 9 vs. 89 +/- 18 mm Hg, p < 0.05) and heart rate increased (150 +/- 16 vs. 118 +/- 24 beats/min, p < 0.01). After glucose-insulin-potassium infusion, ejection fraction area significantly increased (37 +/- 8 vs. 21 +/- 6%, p < 0.0001), without significant changes in mean arterial blood pressure (79 +/- 16 vs. 89 +/- 18 mm Hg, nonsignificant) and heart rate (116 +/- 18 vs. 118 +/- 24 beats/min, nonsignificant). CONCLUSION: Glucose-insulin-potassium was as efficient as dobutamine in improving ventricular systolic function in brain-dead patients, without the side effects of dobutamine.


Subject(s)
Brain Death , Dobutamine/administration & dosage , Heart Failure/drug therapy , Adult , Confidence Intervals , Drug Therapy, Combination , Echocardiography, Doppler , Echocardiography, Transesophageal , Female , Follow-Up Studies , Glucose/administration & dosage , Heart Failure/diagnostic imaging , Heart Failure/prevention & control , Heart Rate/drug effects , Heart Transplantation , Humans , Infusions, Intravenous , Insulin/administration & dosage , Male , Middle Aged , Organ Preservation/methods , Potassium/administration & dosage , Probability , Prospective Studies , Risk Factors , Severity of Illness Index , Stroke Volume/drug effects , Tissue Donors , Treatment Outcome , Ventricular Remodeling/drug effects
16.
Bioorg Med Chem ; 16(6): 2852-69, 2008 Mar 15.
Article in English | MEDLINE | ID: mdl-18226909

ABSTRACT

A large series of piperazin-, piperidin- and tetrahydroisoquinolinamides of 4-(1,3-dialkyl-9-deazaxanthin-8-yl)phenoxyacetic acid were prepared through conventional or multiple parallel syntheses and evaluated for their binding affinity at the recombinant human adenosine receptors, chiefly at the hA(2B) and hA(2A) receptor subtypes. Several ligands endowed with high binding affinity at hA(2B) receptors, excellent selectivity over hA(2A) and hA(3) and a significant, but lower, selectivity over hA(1) were identified. Among them, piperazinamide derivatives 23 and 52, and piperidinamide derivative 69 proved highly potent at hA(2B) (K(i)=11, 2 and 5.5 nM, respectively) and selective towards hA(2A) (hA(2A)/hA(2B) SI=912, 159 and 630, respectively), hA(3) (hA(3)/hA(2B) SI=>100, 3090 and >180, respectively) and hA(1) (hA(1)/hA(2B) SI=>100, 44 and 120, respectively), SI being the selectivity index. A number of selected ligands tested in functional assays in vitro showed very interesting antagonist activities and efficacies at both A(2A) and A(2B) receptor subtypes, with pA(2) values close to the corresponding pK(i)s. Structure-affinity and structure-selectivity relationships suggested that the binding potency at the hA(2B) receptor may be increased by lipophilic substituents at the N4-position of piperazinamides and that an ortho-methoxy substituent at the 8-phenyl ring and alkyl groups at N1 larger than the ones at N3, in the 9-deazaxanthine ring, may strongly enhance the hA(2A)/hA(2B) SI.


Subject(s)
Adenosine A2 Receptor Antagonists , Xanthines/chemistry , Xanthines/pharmacology , Adenosine A3 Receptor Antagonists , Humans , Hydrophobic and Hydrophilic Interactions , Ligands , Protein Binding , Structure-Activity Relationship
17.
J Med Chem ; 50(11): 2732-6, 2007 May 31.
Article in English | MEDLINE | ID: mdl-17469811

ABSTRACT

A novel series of N-heteroaryl 4'-(2-furyl)-4,5'-bipyrimidin-2'-amines has been identified as potent and selective A(2B) adenosine receptor antagonists. In particular, compound 5 showed high affinity for the A(2B) receptor (Ki = 17 nM), good selectivity (IC(50): A(1) > 1000 nM, A(2A) > 2500 nM, A3 > 1000 nM), displayed a favorable pharmacokinetic profile in preclinical species, and showed efficacy in functional in vitro models.


Subject(s)
Adenosine A2 Receptor Antagonists , Furans/chemical synthesis , Pyridines/chemical synthesis , Pyrimidines/chemical synthesis , Animals , Cell Line , Cricetinae , Cricetulus , Dogs , Furans/pharmacokinetics , Furans/pharmacology , Mice , Pyridines/pharmacokinetics , Pyridines/pharmacology , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Radioligand Assay , Rats , Structure-Activity Relationship
18.
Bioorg Med Chem Lett ; 16(14): 3642-5, 2006 Jul 15.
Article in English | MEDLINE | ID: mdl-16697192

ABSTRACT

A new series of 4-(1,3-dialkyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl)benzenesulfonamides has been identified as potent A2B adenosine receptor antagonists. The products have been evaluated for their binding affinities for the human A2B, A1 and A3 adenosine receptors. 6-(4-{[4-(4-Bromobenzyl)piperazin-1-yl]sulfonyl}phenyl)-1,3-dimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (16) showed a high affinity for the A2B adenosine receptor (IC50=1 nM) and selectivity (A1: 183x; A3: 12660x). Synthesis and SAR of this novel class of compounds showing improved absorption properties is presented herein.


Subject(s)
Adenosine A2 Receptor Antagonists , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacology , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Binding, Competitive , Drug Design , Humans , Inhibitory Concentration 50 , Structure-Activity Relationship
19.
J Med Chem ; 49(1): 282-99, 2006 Jan 12.
Article in English | MEDLINE | ID: mdl-16392813

ABSTRACT

Over two hundred 1-, 3-, 8-, and 9-substituted-9-deazaxanthines were prepared and evaluated for their binding affinity at the recombinant human adenosine receptors, in particular at the hA(2B) and hA(2A) subtypes. Several ligands endowed with sub-micromolar to low nanomolar binding affinity at hA(2B) receptors, good selectivity over hA(2A) and hA(3), but a relatively poor selectivity over hA(1) were obtained. Good antagonistic potencies and efficacies, with pA(2) values close to the corresponding pK(i)s, were observed in functional assays in vitro performed on a selected series of compounds. 1,3-Dimethyl-8-phenoxy-(N-p-halogenophenyl)-acetamido-9-deazaxanthine derivatives appeared as the most interesting leads, some of them showing outstanding hA(2B) affinities, high selectivity over hA(2A) and hA(3), but low selectivity over hA(1). Structure-affinity relationships suggested that the binding potency at the hA(2B) receptor was mainly modulated by the steric (lipophilic) properties of the substituents at positions 1 and 3 and by the electronic and lipophilic characteristics of the substituents at position 8. A comparison among affinity and selectivity profiles of 9-deazaxanthines with the corresponding xanthines suggested some possible differences in their binding mode.


Subject(s)
Adenosine A2 Receptor Antagonists , Drug Design , Xanthines/chemical synthesis , Xanthines/pharmacology , Adenosine A1 Receptor Antagonists , Adenosine A3 Receptor Antagonists , Animals , Binding, Competitive/drug effects , CHO Cells , Cell Line , Cricetinae , HeLa Cells , Humans , Molecular Structure , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Xanthines/chemistry
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