RESUMO
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.
Assuntos
Bloqueadores dos Canais de Cálcio/química , Canais de Cálcio/química , Indóis/química , Piridinas/química , Pirróis/química , Animais , Asma , Compostos Aza/química , Bloqueadores dos Canais de Cálcio/farmacocinética , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/imunologia , Indóis/farmacocinética , Indóis/uso terapêutico , Interleucina-2/sangue , Interleucina-2/metabolismo , Células Jurkat , Microssomos/metabolismo , Modelos Biológicos , Ovalbumina/imunologia , Ligação Proteica , Piridinas/farmacocinética , Piridinas/uso terapêutico , Pirróis/farmacocinética , Pirróis/uso terapêutico , Ratos , Relação Estrutura-AtividadeRESUMO
A knowledge-based design strategy led to the discovery of several new series of potent and orally bioavailable CRTh2 antagonists where a bicyclic heteroaromatic ring serves as the central core. Structure-kinetic relationships (SKR) opened up the possibility of long receptor residence times.
Assuntos
Acetatos/química , Compostos Bicíclicos com Pontes/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Acetatos/síntese química , Acetatos/farmacocinética , Animais , Meia-Vida , Humanos , Concentração de Íons de Hidrogênio , Microssomos Hepáticos/metabolismo , Ratos , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Solubilidade , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Acetatos/química , Compostos Bicíclicos com Pontes/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Acetatos/síntese química , Acetatos/farmacocinética , Animais , Meia-Vida , Humanos , Indóis/química , Injeções Intravenosas , Ratos , Ratos Wistar , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relação Estrutura-AtividadeRESUMO
The correct positioning and orientation of an hydrogen bond acceptor (HBA) in the tail portion of the biaryl series of CRTh2 antagonists is a requirement for long receptor residence time. The HBA in combination with a small steric substituent in the core section (R(core) ≠ H) gives access to compounds with dissociation half-lives of ⩾ 24h.
Assuntos
Acetatos/química , Compostos Bicíclicos com Pontes/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Acetatos/síntese química , Acetatos/farmacocinética , Meia-Vida , Humanos , Ligação de Hidrogênio , Modelos Químicos , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Índice de Massa Corporal , Tomada de Decisões Assistida por Computador , Intubação Intratraqueal/efeitos adversos , Intubação Intratraqueal/tendências , Adolescente , Adulto , Idoso , Feminino , Humanos , Intubação Intratraqueal/métodos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de Tempo , Adulto JovemRESUMO
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.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazinas/síntese química , Pirazinas/farmacologia , Adamantano/análogos & derivados , Adamantano/química , Adamantano/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Pirazinas/química , Quinase SykRESUMO
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.
Assuntos
Benzamidas/farmacologia , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Cristalografia por Raios X , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Carbamatos/química , Antagonistas de Receptores Purinérgicos P1 , Xantinas/química , Antagonistas do Receptor A1 de Adenosina , Antagonistas do Receptor A2 de Adenosina , Antagonistas do Receptor A3 de Adenosina , Animais , Carbamatos/síntese química , Carbamatos/farmacologia , Linhagem Celular , Desenho de Fármacos , Humanos , Masculino , Modelos Químicos , Ratos , Ratos Wistar , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/metabolismo , Receptor A2B de Adenosina/metabolismo , Receptor A3 de Adenosina/metabolismo , Receptores Purinérgicos P1/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Xantinas/síntese química , Xantinas/farmacologiaRESUMO
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.
Assuntos
Soluções para Diálise/farmacocinética , Vesículas Extracelulares/metabolismo , Falência Renal Crônica/terapia , Diálise Peritoneal/métodos , Proteômica/métodos , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Cromatografia Líquida , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Falência Renal Crônica/metabolismo , Masculino , Pessoa de Meia-Idade , Peritônio/metabolismo , Espectrometria de Massas em Tandem , Fatores de TempoRESUMO
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.
Assuntos
Morte Encefálica , Dobutamina/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Adulto , Intervalos de Confiança , Quimioterapia Combinada , Ecocardiografia Doppler , Ecocardiografia Transesofagiana , Feminino , Seguimentos , Glucose/administração & dosagem , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/prevenção & controle , Frequência Cardíaca/efeitos dos fármacos , Transplante de Coração , Humanos , Infusões Intravenosas , Insulina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Preservação de Órgãos/métodos , Potássio/administração & dosagem , Probabilidade , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença , Volume Sistólico/efeitos dos fármacos , Doadores de Tecidos , Resultado do Tratamento , Remodelação Ventricular/efeitos dos fármacosRESUMO
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.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Xantinas/química , Xantinas/farmacologia , Antagonistas do Receptor A3 de Adenosina , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Furanos/síntese química , Piridinas/síntese química , Pirimidinas/síntese química , Animais , Linhagem Celular , Cricetinae , Cricetulus , Cães , Furanos/farmacocinética , Furanos/farmacologia , Camundongos , Piridinas/farmacocinética , Piridinas/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ensaio Radioligante , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Vesículas Extracelulares/patologia , Diálise Peritoneal , Peritônio/patologia , Proteoma/análise , Proteômica , Adulto , Idoso , Biomarcadores/análise , Biomarcadores/metabolismo , Vesículas Extracelulares/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Peritoneal/métodos , Peritônio/metabolismo , Proteoma/metabolismo , Proteômica/métodosRESUMO
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.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Desenho de Fármacos , Xantinas/síntese química , Xantinas/farmacologia , Antagonistas do Receptor A1 de Adenosina , Antagonistas do Receptor A3 de Adenosina , Animais , Ligação Competitiva/efeitos dos fármacos , Células CHO , Linhagem Celular , Cricetinae , Células HeLa , Humanos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Xantinas/químicaRESUMO
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.
Assuntos
Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Sulfonas/química , Sulfonas/farmacologia , Relação Dose-Resposta a Droga , Humanos , Cinética , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonas/síntese químicaRESUMO
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.
RESUMO
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).
Assuntos
Aminopiridinas/química , Aminopiridinas/farmacologia , Desenho de Fármacos , Óxidos/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Aminopiridinas/síntese química , Aminopiridinas/uso terapêutico , Animais , Artrite Experimental/sangue , Artrite Experimental/tratamento farmacológico , Domínio Catalítico , Linhagem Celular , Humanos , Concentração Inibidora 50 , Masculino , Modelos Moleculares , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/uso terapêutico , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Especificidade por Substrato , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/sangue , Proteínas Quinases p38 Ativadas por Mitógeno/químicaRESUMO
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.