RESUMO
Cardiovascular instability is common during the reperfusion phase of orthotopic liver transplantation (OLT), and some patients experience a postreperfusion syndrome (PRS). However, there are no reports comparing the cardiac dysfunction between patients with PRS and those without. Thus, the aim of this study was to evaluate cardiac dysfunction in patients exhibiting PRS. This observational retrospective study included 34 patients who underwent OLT and were monitored with transesophageal echocardiography (TEE). The right ventricular/left ventricular (RV/LV) end diastolic area, tricuspid annular plane systolic excursion (TAPSE), left ventricular ejection fraction (LVEF) by Simpson method, pulsed Doppler of the mitral valve, and tissue Doppler motion of the mitral annulus were determined. Echocardiographic measurements were registered at the beginning of surgery and at 1 and 30 min after vascular unclamping. Patients with PRS (PRS group) were identified, and their echocardiographic parameters of ventricular function were compared with those in patients without PRS (non-PRS group). To check the evolution of diastolic-systolic dysfunction, general linear model-repeated measures were estimated. No patient presented systolic/diastolic dysfunction on the basal echocardiogram. One minute after vascular unclamping, the incidence of RV dilation was 4.5 times greater in patients with PRS (Cramer´s V > 0.6), and the incidence of RV systolic dysfunction was 62.5% in patients with PRS compared to 15.40% in patients without PRS (Cramer´s V = 0.45). The incidence of LV systolic dysfunction was 25% in patients with PRS compared to 0% in those without (Cramer´s V = 0.45), and left ventricular diastolic dysfunction was 4.8 times greater in patients with PRS (Cramer´s V = 0.45). No patient presented diastolic dysfunction type III. There were significant differences between groups in the evolutionary pattern at 1 and 30 min after unclamping for RV dilation (p = 0.008) and for TAPSE (p = 0.014). Liver graft reperfusion may alter cardiac function. Cardiac dysfunction was more frequent in patients with PRS. These patients exhibited temporary dysfunction of the RV associated with a varying degree of LV diastolic-systolic dysfunction. Trial registration: clinicaltrials.gov (NCT05175534). January 03, 2022; "retrospectively registered".
Assuntos
Transplante de Fígado , Disfunção Ventricular Esquerda , Disfunção Ventricular Direita , Humanos , Ecocardiografia Transesofagiana , Transplante de Fígado/efeitos adversos , Estudos Retrospectivos , Volume Sistólico , Função Ventricular Esquerda , Função Ventricular Direita , Disfunção Ventricular Esquerda/diagnóstico por imagem , Reperfusão/efeitos adversos , Disfunção Ventricular Direita/diagnóstico por imagem , Disfunção Ventricular Direita/etiologiaRESUMO
Tropomyosin receptor kinases (TrkA, TrkB, TrkC) are activated by hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4). Moreover, the NGF antibody tanezumab has provided clinical proof of concept for inhibition of the TrkA kinase pathway in pain leading to significant interest in the development of small molecule inhibitors of TrkA. However, achieving TrkA subtype selectivity over TrkB and TrkC via a Type I and Type II inhibitor binding mode has proven challenging and Type III or Type IV allosteric inhibitors may present a more promising selectivity design approach. Furthermore, TrkA inhibitors with minimal brain availability are required to deliver an appropriate safety profile. Herein, we describe the discovery of a highly potent, subtype selective, peripherally restricted, efficacious, and well-tolerated series of allosteric TrkA inhibitors that culminated in the delivery of candidate quality compound 23.
Assuntos
Inibidores de Proteínas Quinases/química , Receptor trkA/antagonistas & inibidores , Regulação Alostérica , Sequência de Aminoácidos , Animais , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Ensaios de Triagem em Larga Escala , Humanos , Ligantes , Microssomos Hepáticos/metabolismo , Simulação de Dinâmica Molecular , Ligação Proteica , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Estrutura Terciária de Proteína , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacocinética , Ratos , Receptor trkA/metabolismo , Alinhamento de Sequência , Relação Estrutura-AtividadeRESUMO
This paper describes the design and synthesis of novel, ATP-competitive Akt inhibitors from an elaborated 3-aminopyrrolidine scaffold. Key findings include the discovery of an initial lead that was modestly selective and medicinal chemistry optimization of that lead to provide more selective analogues. Analysis of the data suggested that highly lipophilic analogues would likely suffer from poor overall properties. Central to the discussion is the concept of optimization of lipophilic efficiency and the ability to balance overall druglike propeties with the careful control of lipophilicity in the lead series. Discovery of the nonracemic amide series and subsequent modification produced an advanced analogue that performed well in advanced preclinical assays, including xenograft tumor growth inhibition studies, and this analogue was nominated for clinical development.
Assuntos
Trifosfato de Adenosina/fisiologia , Amidas/síntese química , Aminoquinolinas/síntese química , Antineoplásicos/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Amidas/farmacocinética , Amidas/farmacologia , Aminoquinolinas/farmacocinética , Aminoquinolinas/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Cães , Camundongos , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Based on a high throughput screening hit, pyrrolopyrimidine inhibitors of the Akt kinase are explored. X-ray co-crystal structures of two lead series results in the understanding of key binding interactions, the design of new lead series, and enhanced potency. The syntheses of these series and their biological activities are described. Spiroindoline 13j is found to have an Akt1 kinase IC(50) of 2.4+/-0.6 nM, Akt cell potency of 50+/-19 nM, and provides 68% inhibition of tumor growth in a mouse xenograft model (50 mg/kg, qd, po).
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Animais , Antineoplásicos/química , Técnicas de Química Combinatória , Cristalografia por Raios X , Modelos Animais de Doenças , Desenho de Fármacos , Concentração Inibidora 50 , Camundongos , Conformação Molecular , Estrutura Molecular , Pirimidinas/química , Pirróis/química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
The design, synthesis, and biological evaluation of potent inhibitors of the TrkA kinase is presented. A homology model is created to aid in the enhancement of potency and selectivity of isothiazole inhibitors found during a high-throughput screen. Three different syntheses are utilized to make diverse analogs within this series. Aminoheterocycles are found to be good urea surrogates, whereas bicyclic substituents on the C3 thio group were found to be extremely potent TrkA inhibitors in kinase and cell assays.