RESUMO
Insulin has a narrow therapeutic index, reflected in a small margin between a dose that achieves good glycemic control and one that causes hypoglycemia. Once injected, the clearance of exogenous insulin is invariant regardless of blood glucose, aggravating the potential to cause hypoglycemia. We sought to create a "smart" insulin, one that can alter insulin clearance and hence insulin action in response to blood glucose, mitigating risk for hypoglycemia. The approach added saccharide units to insulin to create insulin analogs with affinity for both the insulin receptor (IR) and mannose receptor C-type 1 (MR), which functions to clear endogenous mannosylated proteins, a principle used to endow insulin analogs with glucose responsivity. Iteration of these efforts culminated in the discovery of MK-2640, and its in vitro and in vivo preclinical properties are detailed in this report. In glucose clamp experiments conducted in healthy dogs, as plasma glucose was lowered stepwise from 280 mg/dL to 80 mg/dL, progressively more MK-2640 was cleared via MR, reducing by â¼30% its availability for binding to the IR. In dose escalations studies in diabetic minipigs, a higher therapeutic index for MK-2640 (threefold) was observed versus regular insulin (1.3-fold).
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Desenho de Fármacos , Hipoglicemiantes/uso terapêutico , Insulina Regular Humana/análogos & derivados , Lectinas Tipo C/agonistas , Lectinas de Ligação a Manose/agonistas , Receptor de Insulina/agonistas , Receptores de Superfície Celular/agonistas , Animais , Animais Endogâmicos , Ligação Competitiva , Células CHO , Cricetulus , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/metabolismo , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Hiperglicemia/prevenção & controle , Hipoglicemia/induzido quimicamente , Hipoglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Insulina Regular Humana/efeitos adversos , Insulina Regular Humana/farmacocinética , Insulina Regular Humana/uso terapêutico , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Ligantes , Masculino , Receptor de Manose , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/metabolismo , Taxa de Depuração Metabólica , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapêutico , Suínos , Porco MiniaturaRESUMO
Niacin is an effective drug for raising HDL cholesterol. However, niacin must be taken in large doses and significant side effects are often observed, including facial flushing, loss of glucose tolerance, and liver toxicity. An anthranilic acid was identified as an agonist of the niacin receptor. In order to improve efficacy and provide structural diversity, replacements for the anthranilic acid were investigated and several compounds with improved properties were identified.
Assuntos
Niacina/metabolismo , Receptores de Droga/metabolismo , ortoaminobenzoatos/química , Disponibilidade BiológicaRESUMO
Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. Compound 1e (MK-6892) displayed excellent receptor activity, good PK across species, remarkably clean off-target profiles, good ancillary pharmacology, and superior therapeutic window over niacin regarding the FFA reduction versus vasodilation in rats and dogs.
Assuntos
Ácidos Carboxílicos/farmacologia , Ácidos Cicloexanocarboxílicos/farmacologia , Cicloexenos/química , Descoberta de Drogas , Oxidiazóis/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Área Sob a Curva , Ligação Competitiva , Células CHO , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Cricetinae , Cricetulus , Ácidos Cicloexanocarboxílicos/química , Ácidos Cicloexanocarboxílicos/farmacocinética , Cães , Avaliação Pré-Clínica de Medicamentos , Ácidos Graxos não Esterificados/sangue , Humanos , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Químicos , Estrutura Molecular , Oxidiazóis/química , Oxidiazóis/farmacocinética , Ratos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Relação Estrutura-Atividade , Vasodilatação/efeitos dos fármacosRESUMO
Novel 1-(2-aminopyrazin-3-yl)methyl-2-thioureas are described as inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2). These compounds demonstrate potent in vitro activity against the enzyme with IC(50) values as low as 15 nM, and suppress expression of TNFalpha in THP-1 cells and in vivo in an acute inflammation model in mice. The synthesis, structure-activity relationship (SAR), and biological evaluation of these compounds are discussed.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Tioureia/química , Animais , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Humanos , Inflamação/tratamento farmacológico , Concentração Inibidora 50 , Camundongos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Relação Estrutura-Atividade , Tioureia/farmacologia , Tioureia/uso terapêutico , Fator de Necrose Tumoral alfa/efeitos dos fármacosRESUMO
INTRODUCTION: GPR109A is the receptor mediating both the antilipolytic and vasodilatory effects of nicotinic acid. In order to develop agonists for GPR109A with improved therapeutic indices we have sought to optimize animal models that evaluate both nicotinic acid-mediated inhibition of lipolysis and stimulation of vasodilatation. The rat and the dog have previously been used to study the antilipolytic effects of nicotinic acid, but no optimal vasodilatation model exits in either species. METHODS: We have developed a vasodilatation model in the rat that measures changes in ear perfusion using laser Doppler flowmetry. In the dog, we have developed a model of vasodilatation measuring changes in red color values in the ear, using a spectrocolorimeter. Effects of GPR109A agonists on lipolysis were measured in both species after oral dosing of compounds, and measuring plasma levels of free fatty acids. RESULTS: In both rat and dog, GPR109A agonists induce dose- and time-dependent vasodilatation, similar to that observed in humans. Vasodilatation is inhibited in both species with cyclooxygenase inhibitors or a specific DP1 receptor antagonist, indicating that, as in man, nicotinic acid-induced vasodilatation in rats and dogs is mainly mediated by the release of PGD(2). DISCUSSION: Our results show that both rat and dog are useful models for the characterization of GPR109A agonists. A therapeutic index for GPR109A agonists can be calculated in either species.
Assuntos
Lipólise/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Vasodilatação/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Monitoramento de Medicamentos/métodos , Ácidos Graxos não Esterificados/sangue , Hipolipemiantes/administração & dosagem , Hipolipemiantes/farmacologia , Indometacina/administração & dosagem , Indometacina/farmacologia , Concentração Inibidora 50 , Injeções Subcutâneas , Masculino , Modelos Animais , Niacina/administração & dosagem , Niacina/farmacologia , Agonistas Nicotínicos/administração & dosagem , Pirazinas/administração & dosagem , Pirazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Nicotínicos/metabolismoRESUMO
A new sub-class of p38 inhibitors represented by 7-amino-naphthyridone have been discovered. Benchmark compound 16 potently inhibited p38 in vitro, was functionally active, and displayed excellent pharmacokinetic profiles in two animal species. Compound 16 reduced inflammation in animal disease models at EC(50) doses as low as 0.2mpk.