RESUMO
A novel class of 1,3,5-pyrazoles has been discovered as potent human glucagon receptor antagonists. Notably, compound 26 is orally bioavailable in several preclinical species and shows selectivity towards cardiac ion channels, other family B receptors such hGIP and hGLP1, and a large panel of enzymes and additional receptors. When dosed orally, compound 26 is efficacious in suppressing glucagon induced plasma glucose excursion in rhesus monkey and transgenic murine pharmacodynamic models at 1 and 10 mpk, respectively.
Assuntos
Pirazóis/química , Receptores de Glucagon/antagonistas & inibidores , Administração Oral , Animais , Glicemia/metabolismo , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Macaca mulatta , Camundongos , Camundongos Transgênicos , Pirazóis/síntese química , Pirazóis/farmacocinética , Ratos , Receptores de Glucagon/metabolismo , Relação Estrutura-AtividadeRESUMO
A new series of thiazole-substituted 1,1,1,3,3,3-hexafluoro-2-propanols were prepared and evaluated as malonyl-CoA decarboxylase (MCD) inhibitors. Key analogs caused dose-dependent decreases in food intake and body weight in obese mice. Acute treatment with these compounds also led to a drop in elevated blood glucose in a murine model of type II diabetes.
Assuntos
Fármacos Antiobesidade/uso terapêutico , Carboxiliases/antagonistas & inibidores , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Hipoglicemiantes/uso terapêutico , Obesidade/tratamento farmacológico , Propanóis/uso terapêutico , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Carboxiliases/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Propanóis/síntese química , Propanóis/química , Propanóis/farmacologia , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologia , Tiazóis/uso terapêuticoRESUMO
AMP-activated protein kinase (AMPK) plays an essential role as a cellular energy sensor and master regulator of metabolism in eukaryotes. Dysregulated lipid and carbohydrate metabolism resulting from insulin resistance leads to hyperglycemia, the hallmark of type 2 diabetes mellitus (T2DM). While pharmacological activation of AMPK is anticipated to improve these parameters, the discovery of selective, direct activators has proven challenging. We now describe a hit-to-lead effort resulting in the discovery of a potent and selective class of benzimidazole-based direct AMPK activators, exemplified by 5-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid, 42 (MK-3903). Compound 42 exhibited robust target engagement in mouse liver following oral dosing, leading to improved lipid metabolism and insulin sensitization in mice.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Benzimidazóis/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Administração Oral , Animais , Benzimidazóis/administração & dosagem , Benzimidazóis/uso terapêutico , Descoberta de Drogas , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , CamundongosRESUMO
Glucagon maintains glucose homeostasis during the fasting state by promoting hepatic gluconeogenesis and glycogenolysis. Hyperglucagonemia and/or an elevated glucagon-to-insulin ratio have been reported in diabetic patients and animals. Antagonizing the glucagon receptor is expected to result in reduced hepatic glucose overproduction, leading to overall glycemic control. Here we report the discovery and characterization of compound 1 (Cpd 1), a compound that inhibits binding of 125I-labeled glucagon to the human glucagon receptor with a half-maximal inhibitory concentration value of 181 +/- 10 nmol/l. In CHO cells overexpressing the human glucagon receptor, Cpd 1 increased the half-maximal effect for glucagon stimulation of adenylyl cyclase with a KDB of 81 +/- 11 nmol/l. In addition, Cpd 1 blocked glucagon-mediated glycogenolysis in primary human hepatocytes. In contrast, a structurally related analog (Cpd 2) was not effective in blocking glucagon-mediated biological effects. Real-time measurement of glycogen synthesis and breakdown in perfused mouse liver showed that Cpd 1 is capable of blocking glucagon-induced glycogenolysis in a dosage-dependent manner. Finally, when dosed in humanized mice, Cpd 1 blocked the rise of glucose levels observed after intraperitoneal administration of exogenous glucagon. Taken together, these data suggest that Cpd 1 is a potent glucagon receptor antagonist that has the capability to block the effects of glucagon in vivo.
Assuntos
Glucagon/antagonistas & inibidores , Receptores de Glucagon/antagonistas & inibidores , Adenilil Ciclases/metabolismo , Animais , Células CHO , Cricetinae , Glucagon/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Cinética , Glicogênio Hepático/metabolismo , Masculino , Camundongos , Camundongos TransgênicosRESUMO
[reaction: see text] A novel approach to alpha,alpha-disubstituted-beta-amino acids (beta(2,2)-amino acids) was employed in the synthesis of a series of 3-(pyrrolidin-1-yl)propionic acids possessing high affinity for the CCR5 receptor and potent anti-HIV activity. The rat pharmacokinetics for these new analogues featured higher bioavailabilities and lower rates of clearance as compared to cyclopentane 1.
Assuntos
Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , Propionatos/farmacologia , Pirrolidinas/farmacologia , Fármacos Anti-HIV/farmacocinética , Disponibilidade Biológica , Propionatos/farmacocinética , Pirrolidinas/farmacocinéticaRESUMO
Prolylcarboxypeptidase (PrCP) is a serine protease that may have a role in metabolism regulation. A class of reversible, potent, and selective PrCP inhibitors was developed starting from a mechanism based design for inhibiting this serine protease. Compound 8o inhibits human and mouse PrCP at IC(50) values of 1 and 2 nM and is not active (IC(50) > 25 µM) against a panel of closely related proteases. It has lower serum binding than its close analogues and is bioavailable in mouse. Subchronic dosing of 8o in PrCP(-/-) and WT mice at 100 mg/kg for 5 days resulted in a 5% reduction in body weight in WT mice and a 1% reduction in PrCP KO mice.
Assuntos
Fármacos Antiobesidade/síntese química , Benzimidazóis/síntese química , Carboxipeptidases/antagonistas & inibidores , Fenilalanina/análogos & derivados , Inibidores de Serina Proteinase/síntese química , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Carboxipeptidases/genética , Desenho de Fármacos , Humanos , Masculino , Camundongos , Camundongos Knockout , Obesidade/tratamento farmacológico , Obesidade/enzimologia , Fenilalanina/síntese química , Fenilalanina/farmacocinética , Fenilalanina/farmacologia , Ligação Proteica , Inibidores de Serina Proteinase/farmacocinética , Inibidores de Serina Proteinase/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
To discover antifungal treatments that possess the desired characteristics of broad spectrum activity, a strong safety profile, and oral bioavailability, new discovery strategies must be implemented to identify structural classes of molecules capable of combating these microorganisms. One such technique that has been implemented is the Candida albicans Fitness Test, a whole cell screening platform capable of delineating the mechanism of action of compounds that demonstrate activity against the clinically relevant pathogenic fungus, C. albicans. Screening crude natural product extracts with this technology has resulted in the identification of a novel family of antifungal natural products, named the parnafungins, which inhibit the enzyme polyadenosine polymerase (PAP), a key component of the mRNA cleavage and polyadenylation complex. Owing to the rapid interconversion of the structural and stereoisomers of the parnafungins at neutral pH, the determination of the structural isomer with the highest affinity for PAP with standard biochemical assays has not been possible. Herein, we present an application of affinity-selection/mass spectrometry (AS-MS) to determine that the "straight" parnafungin structural isomer (parnafungin A) binds preferentially to PAP compared to the "bent" structural isomer (parnafungin B).
Assuntos
Oxazolidinonas/química , Oxazolidinonas/metabolismo , Polinucleotídeo Adenililtransferase/metabolismo , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Cromatografia Líquida , Fungos/enzimologia , Humanos , Isomerismo , Ligantes , Espectrometria de Massas , Oxazolidinonas/análiseRESUMO
Affinity-based selection strategies have recently emerged as a complement to traditional high throughput screening for the rapid discovery of lead compounds for the large number of protein targets emerging from--omics technologies. Herein, we describe a method for the ranking of mixtures of ligands by affinity selection and apply it to rank order a set of inhibitors for the enzyme dipeptidyl peptidase IV.
Assuntos
Química Farmacêutica/métodos , Dipeptidil Peptidase 4/química , Inibidores Enzimáticos/síntese química , Ligantes , Diabetes Mellitus/tratamento farmacológico , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Modelos QuímicosRESUMO
A series of HIV protease inhibitors with modifications on the P3 position have been designed and synthesized. These compounds exhibit excellent antiviral activity against both the wild type enzyme and PI-resistant clinical viral isolates. The synthesis and biological activity of the compounds are described.
Assuntos
Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Linhagem Celular , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Indicadores e Reagentes , Indinavir/síntese química , Indinavir/farmacologia , Relação Estrutura-AtividadeRESUMO
A potent and selective anthrax LF inhibitor 40, (2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide, was identified through SAR study of a high throughput screen lead. It has an IC50 of 54 nM in the enzyme assay and an IC50 of 210 nM in the macrophage cytotoxicity assay. Compound 40 is also effective in vivo in several animal model studies.
Assuntos
Toxinas Bacterianas/antagonistas & inibidores , Piranos/farmacologia , Animais , Antraz/tratamento farmacológico , Antraz/prevenção & controle , Antígenos de Bactérias , Disponibilidade Biológica , Cães , Avaliação Pré-Clínica de Medicamentos , Macaca mulatta , Metaloproteases/antagonistas & inibidores , Camundongos , Estrutura Molecular , Piranos/administração & dosagem , Piranos/síntese química , Coelhos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel class of antagonists of the human glucagon receptor (hGCGR) has been discovered. Systematic modification of the lead compound identified substituents that were essential for activity and those that were amenable to further optimization. This SAR exploration resulted in the synthesis of 13, which exhibited good potency as an hGCGR functional antagonist (IC50 = 34 nM) and moderate bioavailability (36% in mice).
Assuntos
Receptores de Glucagon/antagonistas & inibidores , Tiofenos/síntese química , Tiofenos/farmacologia , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tiofenos/classificaçãoRESUMO
Ezetimibe is a potent inhibitor of cholesterol absorption that has been approved for the treatment of hypercholesterolemia, but its molecular target has been elusive. Using a genetic approach, we recently identified Niemann-Pick C1-Like 1 (NPC1L1) as a critical mediator of cholesterol absorption and an essential component of the ezetimibe-sensitive pathway. To determine whether NPC1L1 is the direct molecular target of ezetimibe, we have developed a binding assay and shown that labeled ezetimibe glucuronide binds specifically to a single site in brush border membranes and to human embryonic kidney 293 cells expressing NPC1L1. Moreover, the binding affinities of ezetimibe and several key analogs to recombinant NPC1L1 are virtually identical to those observed for native enterocyte membranes. KD values of ezetimibe glucuronide for mouse, rat, rhesus monkey, and human NPC1L1 are 12,000, 540, 40, and 220 nM, respectively. Last, ezetimibe no longer binds to membranes from NPC1L1 knockout mice. These results unequivocally establish NPC1L1 as the direct target of ezetimibe and should facilitate efforts to identify the molecular mechanism of cholesterol transport.
Assuntos
Azetidinas/farmacologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Proteínas/metabolismo , Animais , Azetidinas/química , Sítios de Ligação , Linhagem Celular , Membrana Celular/metabolismo , Enterócitos/citologia , Enterócitos/metabolismo , Ezetimiba , Humanos , Mucosa Intestinal/metabolismo , Intestinos/citologia , Macaca mulatta , Proteínas de Membrana/genética , Proteínas de Membrana Transportadoras/deficiência , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Endogâmicos C57BL , Microvilosidades/metabolismo , Doenças de Niemann-Pick , Ligação Proteica , Proteínas/genética , Ratos , Ratos Sprague-Dawley , Especificidade da EspécieRESUMO
A novel class of spiro-ureas has been discovered as potent human glucagon receptor antagonists in both binding and functional assays. Preliminary studies have revealed that compound 15 is an orally active human glucagon receptor antagonist in a transgenic murine pharmacodynamic model at 10 and 30 mpk. Compound 15 is orally bioavailable in several preclinical species and shows selectivity toward cardiac ion channels and other family B receptors, such as hGIP1 and hGLP.
Assuntos
Receptores de Glucagon/antagonistas & inibidores , Compostos de Espiro/farmacologia , Ureia/farmacologia , Administração Oral , Animais , Células CHO , Cricetinae , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Compostos de Espiro/química , Ureia/químicaRESUMO
A novel class of small molecule human granzyme B inhibitors is reported. Compound 20 has a K(i) of 7 nM against human granzyme B and blocks CTL mediated apoptosis with an IC(50) of 3 micromolar.
Assuntos
Apoptose/efeitos dos fármacos , Serina Endopeptidases/metabolismo , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Citotoxicidade Imunológica/efeitos dos fármacos , Desenho de Fármacos , Granzimas , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
The synthesis of a series of novel dihdyropyridine diacid glycogen phosphorylase inhibitors is presented. SAR and functional assay data are discussed, along with the effect of a single inhibitor on blood glucose in a diabetic animal model.
Assuntos
Glicemia/análise , Di-Hidropiridinas/química , Inibidores Enzimáticos/farmacologia , Glicogênio Fosforilase/antagonistas & inibidores , Hipoglicemiantes/farmacologia , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Modelos Animais de Doenças , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , CamundongosRESUMO
Replacement of the pyridylmethyl moiety in indinavir with a pyridyl oxazole yielded HIV-1 protease inhibitors (PI) with greatly improved potency against PI-resistant HIV-1 strains. A meta-methoxy group on the pyridyl ring and a gem-dimethyl methyl linkage afforded compound 10 with notable in vitro antiviral activity against HIV-1 viral strains with reduced susceptibility to the clinically available PIs. Compound 10 also demonstrated favorable in vivo pharmacokinetics in animal models.
Assuntos
Farmacorresistência Viral , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Animais , Disponibilidade Biológica , Linhagem Celular , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Cães , Inibidores da Protease de HIV/farmacocinética , HIV-1/enzimologia , Humanos , Técnicas In Vitro , Indinavir/farmacocinética , Indinavir/farmacologia , Macaca mulatta , Microssomos Hepáticos/metabolismo , Ratos , Linfócitos T/efeitos dos fármacos , Linfócitos T/virologiaRESUMO
The preparation of a series of substituted indoles coupled to six- and seven-membered cyclic lactams is described and their role as human glycogen phosphorylase a inhibitors discussed. The SAR of the indole moiety and lactam ring are presented.
Assuntos
Inibidores Enzimáticos/farmacologia , Glicogênio Fosforilase/antagonistas & inibidores , Quinolinas/síntese química , Quinolinas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Cinética , Modelos Moleculares , Conformação Molecular , Quinolinas/química , Relação Estrutura-AtividadeRESUMO
Preparation and screening of mixture libraries based on a 2-arylindole scaffold resulted in the discovery of potent ligands for a variety of G-protein coupled receptors.
Assuntos
Técnicas de Química Combinatória , Indóis/síntese química , Indóis/farmacologia , Receptores de Superfície Celular/metabolismo , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Aminas/síntese química , Aminas/química , Aminas/farmacologia , Ligação Competitiva/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Proteínas de Ligação ao GTP , Humanos , Indóis/química , Ligantes , Receptores de Quimiocinas/metabolismo , Receptores de Serotonina/metabolismo , Receptores de Taquicininas/metabolismo , Relação Estrutura-AtividadeRESUMO
A 1X22X41 combinatorial library or 902 compounds of indinavir analogues was synthesized on the solid support to identify a replacement for the aminoindanol moiety at P2'. 2,6-Dimethyl-4-hydroxy phenol was discovered to be a good replacement for aminoindanol.
Assuntos
Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , Indinavir/análogos & derivados , Indinavir/síntese química , Técnicas de Química Combinatória , Protease de HIV/química , Protease de HIV/efeitos dos fármacos , Inibidores da Protease de HIV/farmacocinética , Humanos , Indicadores e Reagentes , Indinavir/farmacocinética , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
Indinavir analogues with blocked metabolism sites show highly improved pharmacokinetic profiles in animals. The cis-aminochromanol substituted analogues exhibited excellent potency against both the wild-type (NL4-3) virus and protease inhibitor-resistant HIV strains.