RESUMO
We have identified a series of novel insulin receptor partial agonists (IRPAs) with a potential to mitigate the risk of hypoglycemia associated with the use of insulin as an antidiabetic treatment. These molecules were designed as dimers of native insulin connected via chemical linkers of variable lengths with optional capping groups at the N-terminals of insulin chains. Depending on the structure, the maximal activation level (%Max) varied in the range of â¼20-70% of native insulin, and EC50 values remained in sub-nM range. Studies in minipig and dog demonstrated that IRPAs had sufficient efficacy to normalize plasma glucose levels in diabetes, while providing reduction of hypoglycemia risk. IRPAs had a prolonged duration of action, potentially making them suitable for once-daily dosing. Two lead compounds with %Max values of 30 and 40% relative to native insulin were selected for follow up studies in the clinic.
Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemia , Animais , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cães , Hipoglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Receptor de Insulina , Suínos , Porco Miniatura , Índice TerapêuticoRESUMO
The amination of aryl halides has become one of the most commonly practiced C-N bond-forming reactions in pharmaceutical and laboratory syntheses. The widespread use of strong or poorly soluble inorganic bases for amine activation nevertheless complicates the compatibility of this important reaction class with sensitive substrates as well as applications in flow and automated synthesis, to name a few. We report a palladium-catalyzed C-N coupling using Et3N as a weak, soluble base, which allows a broad substrate scope that includes bromo- and chloro(hetero)arenes, primary anilines, secondary amines, and amide type nucleophiles together with tolerance for a range of base-sensitive functional groups. Mechanistic data have established a unique pathway for these reactions in which water serves multiple beneficial roles. In particular, ionization of a neutral catalytic intermediate via halide displacement by H2O generates, after proton loss, a coordinatively unsaturated Pd-OH species that can bind amine substrate triggering intramolecular N-H heterolysis. This water-assisted pathway operates efficiently with even weak terminal bases, such as Et3N. The use of a simple, commercially available ligand, PAd3, is key to this water-assisted mechanism by promoting coordinative unsaturation in catalytic intermediates responsible for the heterolytic activation of strong element-hydrogen bonds, which enables broad compatibility of carbon-heteroatom cross-coupling reactions with sensitive substrates and functionality.
Assuntos
Aminas/química , Água/química , Aminação , Carbono/química , Catálise , Ligantes , Nitrogênio/química , Paládio/químicaRESUMO
We describe our optimization efforts to improve the physicochemical properties, solubility, and off-target profile of 1, an inhibitor of TarO, an early stage enzyme in the biosynthetic pathway for wall teichoic acid (WTA) synthesis. Compound 1 displayed a TarO IC50 of 125 nM in an enzyme assay and possessed very high lipophilicity (clogP = 7.1) with no measurable solubility in PBS buffer. Structure-activity relationship (SAR) studies resulted in a series of compounds with improved lipophilic ligand efficiency (LLE) consistent with the reduction of clogP. From these efforts, analog 9 was selected for our initial in vivo study, which in combination with subefficacious dose of imipenem (IPM) robustly lowered the bacterial burden in a neutropenic Staphylococci murine infection model. Concurrent with our in vivo optimization effort using 9, we further improved LLE as exemplified by a much more druglike analog 26.
Assuntos
Lipídeos/química , Bibliotecas de Moléculas Pequenas , Animais , Feminino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Solubilidade , Relação Estrutura-AtividadeRESUMO
The discovery of novel 4-hydroxy-2-(heterocyclic)pyrimidine-5-carboxamide inhibitors of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD) is described. These are potent, selective, orally bioavailable across several species, and active in stimulating erythropoiesis. Mouse and rat studies showed hematological changes with elevations of plasma EPO and circulating reticulocytes following single oral dose administration, while 4-week q.d. po administration in rat elevated hemoglobin levels. A major focus of the optimization process was to decrease the long half-life observed in higher species with early compounds. These efforts led to the identification of 28 (MK-8617), which has advanced to human clinical trials for anemia.
Assuntos
Anemia/tratamento farmacológico , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Piridazinas/farmacologia , Pirimidinas/farmacologia , Administração Oral , Anemia/enzimologia , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Piridazinas/administração & dosagem , Piridazinas/química , Pirimidinas/administração & dosagem , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
The synthesis, SAR, binding affinities and pharmacokinetic profiles are described for a series of cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors discovered by high throughput screening. Compounds show high levels of ex vivo target engagement in mouse plasma 20 h post oral dose.
Assuntos
Carboxipeptidases/antagonistas & inibidores , Cicloexanos/química , Cicloexanos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Animais , Cicloexanos/farmacocinética , Descoberta de Drogas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Obesidade/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Synthesis and structure-activity relationships of cannabinoid-1 receptor (CB1R) inverse agonists based on dihydro-pyrano[2,3-b] pyridine and tetrahydro-1,8-naphtyridine scaffolds are presented. Rat food intake and pharmacokinetic evaluation of 13g, 13i, 13k and 17a revealed these compounds to be highly efficacious orally active modulators of CB1R.
Assuntos
Naftiridinas/química , Piridinas/química , Receptor CB1 de Canabinoide/agonistas , Redução de Peso/efeitos dos fármacos , Administração Oral , Animais , Ingestão de Alimentos , Humanos , Naftiridinas/síntese química , Naftiridinas/farmacologia , Farmacocinética , Piridinas/síntese química , Piridinas/farmacologia , Ratos , Receptor CB1 de Canabinoide/efeitos dos fármacos , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
This paper describes the discovery of N-[(4R)-6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]-5-methyl-1H-pyrazole-3-carboxamide (MK-5596, 12c) as a novel cannabinoid-1 receptor (CB1R) inverse agonist for the treatment of obesity. Structure-activity relationship (SAR) studies of lead compound 3, which had off-target hERG (human ether-a-go-go related gene) inhibition activity, led to the identification of several compounds that not only had attenuated hERG inhibition activity but also were subject to glucuronidation in vitro providing the potential for multiple metabolic clearance pathways. Among them, pyrazole 12c was found to be a highly selective CB1R inverse agonist that reduced body weight and food intake in a DIO (diet-induced obese) rat model through a CB1R-mediated mechanism. Although 12c was a substrate of P-glycoprotein (P-gp) transporter, its high in vivo efficacy in rodents, good pharmacokinetic properties in preclinical species, good safety margins, and its potential for a balanced metabolism profile in man allowed for the further evaluation of this compound in the clinic.
Assuntos
Fármacos Antiobesidade/síntese química , Piranos/síntese química , Piridinas/síntese química , Receptor CB1 de Canabinoide/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Ligação Competitiva , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Cricetinae , Cricetulus , Cristalografia por Raios X , Cães , Agonismo Inverso de Drogas , Ingestão de Alimentos/efeitos dos fármacos , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Glucuronídeos/metabolismo , Haplorrinos , Hepatócitos/metabolismo , Humanos , Camundongos , Camundongos Knockout , Modelos Moleculares , Conformação Molecular , Piranos/farmacocinética , Piranos/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Receptor CB1 de Canabinoide/genética , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The synthesis, SAR and binding affinities of cannabinoid-1 receptor (CB1R) inverse agonists based on furo[2,3-b]pyridine scaffolds are described. Food intake, mechanism specific efficacy, pharmacokinetic, and metabolic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.
Assuntos
Desenho de Fármacos , Furanos/síntese química , Piridinas/síntese química , Receptor CB1 de Canabinoide/agonistas , Animais , Benzopiranos , Cães , Furanos/química , Furanos/farmacologia , Haplorrinos , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Knockout , Estrutura Molecular , Piridinas/química , Piridinas/farmacologia , Ratos , Receptor CB1 de Canabinoide/genética , Relação Estrutura-AtividadeRESUMO
MRL-1, a cannabinoid receptor-1 inverse agonist, was a member of a lead candidate series for the treatment of obesity. In rats, MRL-1 is eliminated mainly via metabolism, followed by excretion of the metabolites into bile. The major metabolite M1, a glutathione conjugate of MRL-1, was isolated and characterized by liquid chromatography/mass spectrometry and NMR spectroscopic methods. The data suggest that the t-butylsulfonyl group at C-2 of furopyridine was displaced by the glutathionyl group. In vitro experiments using rat and monkey liver microsomes in the presence of reduced glutathione (GSH) showed that the formation of M1 was independent of NADPH and molecular oxygen, suggesting that this reaction was not mediated by an oxidative reaction and a glutathione S-transferase (GST) was likely involved in catalyzing this reaction. Furthermore, a rat hepatic GST was capable of catalyzing the conversion of MRL-1 to M1 in the presence of GSH. When a close analog of MRL-1, a p-chlorobenzenesulfonyl furopyridine derivative (MRL-2), was incubated with rat liver microsomes in the presence of GSH, p-chlorobenzene sulfinic acid (M2) was also identified as a product in addition to the expected M1. Based on these data, a mechanism is proposed involving direct nucleophilic addition of GSH to sulfonylfuropyridine, resulting in an unstable adduct that spontaneously decomposes to form M1 and M2.
Assuntos
Biocatálise , Glutationa Transferase/metabolismo , Piridinas/farmacocinética , Compostos de Enxofre/farmacocinética , Animais , Bile/química , Biotransformação/fisiologia , Cromatografia Líquida , Citosol/metabolismo , Cães , Glutationa/metabolismo , Haplorrinos , Humanos , Fígado/enzimologia , Espectroscopia de Ressonância Magnética , Masculino , Microssomos Hepáticos/enzimologia , Estrutura Molecular , NADP/metabolismo , Piridinas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/antagonistas & inibidores , Especificidade da Espécie , Compostos de Enxofre/metabolismo , Espectrometria de Massas em TandemRESUMO
The synthesis, SAR and binding affinities are described for cannabinoid-1 receptor (CB1R) specific inverse agonists based on pyridopyrimidine and heterotricyclic scaffolds. Food intake and pharmacokinetic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.
Assuntos
Agonistas de Receptores de Canabinoides , Obesidade/tratamento farmacológico , Pirimidinas/química , Administração Oral , Animais , Canabinoides/química , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Estrutura Terciária de Proteína , Ratos , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistas , Relação Estrutura-AtividadeRESUMO
Optimization of the biological activity for 5,6-diarylpyridines as CB1 receptor inverse agonists is described. Food intake and pharmacokinetic evaluation of 3f and 15c indicate that these compounds are effective orally active modulators of CB1.
Assuntos
Química Farmacêutica/métodos , Piridinas/química , Piridinas/síntese química , Receptor CB1 de Canabinoide/agonistas , Animais , Comportamento Animal/efeitos dos fármacos , Desenho de Fármacos , Comportamento Alimentar/efeitos dos fármacos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Temperatura , Tolueno/químicaRESUMO
Synthesis, SAR, and binding affinities are described for a new class of 1,8-naphthyridinone CB1 receptor specific inverse agonists. Food intake, knockout mouse, and pharmacokinetic evaluation of 14 indicate that this compound is an effective orally active modulator of CB1.