RESUMO
Physical activity promotes metabolic and cardiovascular health benefits that derive in part from the transcriptional responses to exercise that occur within skeletal muscle and other organs. There is interest in discovering a pharmacologic exercise mimetic that could imbue wellness and alleviate disease burden. However, the molecular physiology by which exercise signals the transcriptional response is highly complex, making it challenging to identify a single target for pharmacological mimicry. The current studies evaluated the transcriptome responses in skeletal muscle, heart, liver, and white and brown adipose to novel small molecule activators of AMPK (pan-activators for all AMPK isoforms) compared to that of exercise. A striking level of congruence between exercise and pharmacological AMPK activation was observed across the induced transcriptome of these five tissues. However, differences in acute metabolic response between exercise and pharmacologic AMPK activation were observed, notably for acute glycogen balances and related to the energy expenditure induced by exercise but not pharmacologic AMPK activation. Nevertheless, intervention with repeated daily administration of short-acting activation of AMPK was found to mitigate hyperglycemia and hyperinsulinemia in four rodent models of metabolic disease and without the cardiac glycogen accretion noted with sustained pharmacologic AMPK activation. These findings affirm that activation of AMPK is a key node governing exercise mediated transcription and is an attractive target as an exercise mimetic.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo/metabolismo , Fígado/metabolismo , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Animais , Metabolismo Energético , Ativação Enzimática/efeitos dos fármacos , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Homeostase , Camundongos Endogâmicos C57BL , Oxirredução , Condicionamento Físico AnimalRESUMO
A class of 3,5-diphenyl-1,2,4-oxadiazole based compounds have been identified as potent sphingosine-1-phosphate-1 (S1P1) receptor agonists with minimal affinity for the S1P2 and S1P3 receptor subtypes. Analogue 26 (S1P1 IC50 = 0.6 nM) has an excellent pharmacokinetics profile in the rat and dog and is efficacious in a rat skin transplant model, indicating that S1P3 receptor agonism is not a component of immunosuppressive efficacy.
Assuntos
Imunossupressores/síntese química , Oxidiazóis/síntese química , Receptores de Lisoesfingolipídeo/agonistas , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Sobrevivência de Enxerto , Imunossupressores/farmacocinética , Imunossupressores/farmacologia , Contagem de Linfócitos , Oxidiazóis/farmacocinética , Oxidiazóis/farmacologia , Ensaio Radioligante , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Transplante de Pele , Relação Estrutura-AtividadeRESUMO
Moderately potent, selective S1P(1) receptor agonists identified from high-throughput screening have been adapted into lipophilic tails for a class of orally bioavailable amino acid-based S1P(1) agonists represented by 7. Many of the new compounds are potent S1P(1) agonists that select against the S1P(2), S1P(3), and S1P(4) (although not S1P(5)) receptor subtypes. Analogues 18 and 24 are highly orally bioavailable and possess excellent pharmacokinetic profiles in the rat, dog, and rhesus monkey.
Assuntos
Azetidinas/farmacologia , Imunossupressores/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Administração Oral , Animais , Azetidinas/farmacocinética , Disponibilidade Biológica , Células CHO , Cricetinae , Cães , Desenho de Fármacos , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Imunossupressores/farmacocinética , Linfócitos/efeitos dos fármacos , Macaca mulatta , Camundongos , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-AtividadeRESUMO
Structure-activity relationship (SAR) studies of 3-arylpropionic acids-a class of novel S1P(1) selective agonists-by introducing substitution to the propionic acid chain and replacing the adjacent phenyl ring with pyridine led to a series of modified 3-arylpropionic acids with enhanced half-life in rat. These analogs (e.g., cyclopropanecarboxylic acids) exhibited longer half-life in rat than did unmodified 3-arylpropionic acids. This result suggests that metabolic oxidation at the propionic acid chain, particularly at the C3 benzylic position of 3-arylpropionic acids, is probably responsible for their short half-life in rodent.
Assuntos
Propionatos/síntese química , Propionatos/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Animais , Disponibilidade Biológica , Células CHO , Cricetinae , Cricetulus , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Meia-Vida , Contagem de Linfócitos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A series of 2,5-cis-disubstituted pyrrolidines were synthesized and evaluated as S1P receptor agonists. Compounds 15-21 were identified with good selectivity over S1P3 which lowered circulating lymphocytes after oral administration in mice.
Assuntos
Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Pirrolidinas/química , Receptores de Lisoesfingolipídeo/agonistas , Administração Oral , Animais , Ácidos Carboxílicos/síntese química , Estrutura Molecular , Ratos , Receptores de Lisoesfingolipídeo/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of 2-aryl(pyrrolidin-4-yl)acetic acids were synthesized and their biological activities were evaluated as agonists of S1P receptors. These analogs were able to induce lowering of lymphocyte counts in the peripheral blood of mice and were found to have good overall pharmacokinetic properties in rat.
Assuntos
Acetatos/farmacologia , Pirrolidinas/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Acetatos/síntese química , Acetatos/química , Animais , Contagem de Linfócitos , Lisofosfolipídeos/antagonistas & inibidores , Camundongos , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Pirrolidinas/síntese química , Pirrolidinas/química , Ratos , Esfingosina/análogos & derivados , Esfingosina/antagonistas & inibidores , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Novel series of sphingosine-1-phosphate (S1P) receptor agonists were developed through a systematic SAR aimed to achieve high selectivity for a single member of the S1P family of receptors, S1P1. The optimized structure represents a highly S1P1-selective and efficacious agonist: S1P1/S1P2, S1P1/S1P3, S1P1/S1P4>10,000-fold, S1P1/S1P5>600-fold, while EC50 (S1P1) <0.2 nM. In vivo experiments are consistent with S1P1 receptor agonism alone being sufficient for achieving desired lymphocyte-lowering effect.
Assuntos
Imunossupressores/síntese química , Imunossupressores/farmacologia , Linfócitos/efeitos dos fármacos , Receptores de Lisoesfingolipídeo/agonistas , Animais , Células CHO , Cricetinae , Contagem de Linfócitos , Linfócitos/citologia , Relação Estrutura-AtividadeRESUMO
A series of 3-arylpropionic acids were synthesized as S1P1 receptor agonists. Structure-activity relationship studies on the pendant phenyl ring revealed several structural features offering selectivity of S1P1 binding against S1P2-5. These highly selective S1P1 agonists induced peripheral blood lymphocyte lowering in mice and one of them was found to be efficacious in a rat skin transplantation model, supporting that S1P1 agonism is primarily responsible for the immunosuppressive efficacy observed in preclinical animal models.
Assuntos
Imunossupressores/farmacologia , Fenilpropionatos/síntese química , Fenilpropionatos/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Animais , Células CHO , Cricetinae , Ligantes , Contagem de Linfócitos/veterinária , Camundongos , Ratos , Transplante de Pele , Relação Estrutura-AtividadeRESUMO
A series of conformationally constrained 3-(N-alkylamino)propylphosphonic acids were systematically synthesized and their activities as S1P receptor agonists were evaluated. Several pyrrolidine and cyclohexane analogs had S1P receptor profiles comparable to the acyclic lead compound, 3-(N-tetradecylamino)propylphosphonic acid (3), lowered circulating lymphocytes in mice after iv administration and were thus identified as being suitable for further investigations.