RESUMO
A series of novel (R)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines were identified as potent and selective agonists of the 5-HT2C receptor. Optimizations performed on a previously reported series of racemic tetrahydroquinoline-based tricyclic amines, delivered an advanced drug lead, (R)-4-(3,3,3-trifluoropropyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine, which displayed excellent in vitro and in vivo pharmacological profiles.
Assuntos
Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Relação Dose-Resposta a Droga , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Agonistas do Receptor 5-HT2 de Serotonina/química , Relação Estrutura-AtividadeRESUMO
Modulators of S1P1 have proven utility for the treatment of autoimmune disease and efforts to identify new agents with improved safety and pharmacokinetic parameters are ongoing. Several new S1P1 chemotypes were designed and optimized for potency and oral bioavailability. These new agents are characterized by a 'tricyclic fused indole array' and are highly potent agonists of the S1P1 receptor.
Assuntos
Desenho de Fármacos , Indóis/química , Receptores de Lisoesfingolipídeo/agonistas , Animais , Cães , Meia-Vida , Humanos , Indóis/síntese química , Indóis/farmacocinética , Camundongos , Ligação Proteica , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Lisoesfingolipídeo/metabolismo , Relação Estrutura-AtividadeRESUMO
Two series of fused tricyclic indoles were identified as potent and selective S1P(1) agonists. In vivo these agonists produced a significant reduction in circulating lymphocytes which translated into robust efficacy in several rodent models of autoimmune disease. Importantly, these agonists were devoid of any activity at the S1P(3) receptor in vitro, and correspondingly did not produce S1P(3) mediated bradycardia in telemeterized rat.
Assuntos
Fatores Imunológicos/química , Indóis/química , Receptores de Lisoesfingolipídeo/agonistas , Animais , Doenças Autoimunes/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Humanos , Fatores Imunológicos/farmacocinética , Fatores Imunológicos/uso terapêutico , Indóis/farmacocinética , Indóis/uso terapêutico , Linfócitos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Lisoesfingolipídeo/metabolismo , Relação Estrutura-AtividadeRESUMO
S1P(1) receptor driven lymphopenia has proven utility in the treatment of an array of autoimmune disease states. As a part of our efforts to develop potent and selective S1P(1) receptor agonists, we have identified a novel chemical series of 4-oxo-4-(5-(5-phenyl-1,2,4-oxadiazol-3-yl)indolin-1-yl)butanoic acid S1P(1) receptor agonists.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Butiratos/síntese química , Butiratos/farmacologia , Imunossupressores/síntese química , Imunossupressores/farmacologia , Indóis/síntese química , Indóis/farmacologia , Linfócitos/metabolismo , Proteínas do Tecido Nervoso/agonistas , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Proteínas de Ligação a RNA/agonistas , Animais , Butiratos/farmacocinética , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Haplorrinos , Ensaios de Triagem em Larga Escala , Humanos , Imunossupressores/farmacocinética , Indóis/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas do Tecido Nervoso/química , Oxidiazóis/farmacocinética , Proteínas de Ligação a RNA/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
The discovery of a novel, selective and fully efficacious CB2 agonist with satisfactory pharmacokinetic and pharmaceutical properties is described. Compound 6 was efficacious in a rat model of osteoarthritis pain following oral administration and, in contrast to morphine, maintained its analgesic effect throughout a 5-day subchronic treatment paradigm. These data were consistent with our hypothesis that full agonist efficacy is required for efficient internalization and recycling of the CB2 receptor to avoid tachyphylaxis. Based on its overall favorable preclinical profile, 6 (APD371) was selected for further development for the treatment of pain.
RESUMO
APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P1 and has a favorable PK/PD profile, producing robust lymphocyte lowering at relatively low plasma concentrations in several preclinical species. This new agent was efficacious in a mouse experimental autoimmune encephalomyelitis (EAE) model of MS and a rat collagen induced arthritis (CIA) model and was found to have appreciable central exposure.
RESUMO
S1P1 is a validated target for treatment of autoimmune disease, and functional antagonists with superior safety and pharmacokinetic properties are being sought as second generation therapeutics. We describe the discovery and optimization of (7-benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acids as potent, centrally available, direct acting S1P1 functional antagonists, with favorable pharmacokinetic and safety properties.
RESUMO
To further explore the limitations to maximal O(2) consumption (.VO(2 max)) in exercise-trained skeletal muscle, six cyclists performed graded knee-extensor exercise to maximum work rate (WR(max)) in hypoxia (12% O(2)), hyperoxia (100% O(2)), and hyperoxia + femoral arterial infusion of adenosine (ADO) at 80% WR(max). Arterial and venous blood sampling and thermodilution blood flow measurements allowed the determination of muscle O(2) delivery and O(2) consumption. At WR(max), O(2) delivery rose progressively from hypoxia (1.0 +/- 0.04 l/min) to hyperoxia (1.20 +/- 0.09 l/min) and hyperoxia + ADO (1.33 +/- 0.05 l/min). Leg .VO(2 max) varied with O(2) availability (0.81 +/- 0.05 and 0.97 +/- 0.07 l/min in hypoxia and hyperoxia, respectively) but did not improve with ADO-mediated vasodilation (0.80 +/- 0.09 l/min in hyperoxia + ADO). Although a vasodilatory reserve in the maximally working quadriceps muscle group may have been evidenced by increased leg vascular conductance after ADO infusion beyond that observed in hyperoxia (increased blood flow but no change in blood pressure), we recognize the possibility that the ADO infusion may have provoked vasodilation in nonexercising tissue of this limb. Together, these findings imply that maximally exercising skeletal muscle may maintain some vasodilatory capacity, but the lack of improvement in leg .VO(2 max) with significantly increased O(2) delivery (hyperoxia + ADO), with a degree of uncertainty as to the site of this dilation, suggests an ADO-induced mismatch between O(2) consumption and blood flow in the exercising limb.
Assuntos
Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/fisiologia , Consumo de Oxigênio/fisiologia , Oxigênio/metabolismo , Resistência Física/fisiologia , Esforço Físico/fisiologia , Vasodilatação/fisiologia , Adulto , Humanos , MasculinoRESUMO
Incremental knee extensor (KE) exercise performed at 25, 70, and 100% of single-leg maximal work rate (WR(MAX)) was combined with ex vivo electron paramagnetic resonance (EPR) spectroscopic detection of alpha-phenyl-tert-butylnitrone (PBN) adducts, lipid hydroperoxides (LH), and associated parameters in five males. Blood samples were taken from the femoral arterial and venous circulation that, when combined with measured changes in femoral venous blood flow, permitted a direct examination of oxidant exchange across a functionally isolated contracting muscle bed. KE exercise progressively increased the net outflow of LH and PBN adducts (100% > 70% > 25% WR(MAX), P < 0.05) consistent with the generation of secondary, lipid-derived oxygen (O(2))-centered alkoxyl and carbon-centered alkyl radicals. Radical outflow appeared to be more intimately associated with predicted decreases in intracellular Po(2) (iPo(2)) as opposed to measured increases in leg O(2) uptake, with greater outflow recorded between 25 and 70% WR(MAX) (P < 0.05 vs. 70-100% WR(MAX)). This bias was confirmed when radical venoarterial concentration differences were expressed relative to changes in the convective components of O(2) extraction and flow (25-70% WR(MAX) P < 0.05 vs. 70-100% WR(MAX), P > 0.05). Exercise also resulted in a net outflow of other potentially related redox-reactive parameters, including hydrogen ions, norepinephrine, myoglobin, lactate dehydrogenase, and uric acid, whereas exchange of lipid/lipoproteins, ascorbic acid, and selected lipid-soluble anti-oxidants was unremarkable. These findings provide direct evidence for an exercise intensity-dependent increase in free radical outflow across an active muscle bed that was associated with an increase in sarcolemmal membrane permeability. In addition to increased mitochondrial electron flux subsequent to an increase in O(2) extraction and flow, exercise-induced free radical generation may also be regulated by changes in iPo(2), hydrogen ion generation, norepinephrine autoxidation, peroxidation of damaged tissue, and xanthine oxidase activation.