RESUMO
Halosalicylamide derivatives were identified from high-throughput screening as potent inhibitors of HCV NS5B polymerase. The subsequent structure and activity relationship revealed the absolute requirement of the salicylamide moiety for optimum activity. Methylation of either the hydroxyl group or the amide group of the salicylamide moiety abolished the activity while the substitutions on both phenyl rings are acceptable. The halosalicylamide derivatives were shown to be non-competitive with respect to elongation nucleotide and demonstrated broad genotype activity against genotype 1-3 HCV NS5B polymerases. Inhibitor competition studies indicated an additive binding mode to the initiation pocket that is occupied by the thiadiazine class of compounds and an additive binding mode to the elongation pocket that is occupied by diketoacids, but a mutually exclusive binding mode with respect to the allosteric thumb pocket that is occupied by the benzimidazole class of inhibitors. Therefore, halosalicylamides represent a novel class of allosteric inhibitors of HCV NS5B polymerase.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Salicilamidas/síntese química , Salicilamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Estrutura Molecular , Salicilamidas/química , Relação Estrutura-AtividadeRESUMO
A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine (C5-Pro-Pro) analogues was discovered as dipeptidyl peptidase IV (DPPIV) inhibitors as a potential treatment of diabetes and obesity. X-ray crystallography data show that these inhibitors bind to the catalytic site of DPPIV with the cyano group forming a covalent bond with the serine residue of DPPIV. The C5-substituents make various interactions with the enzyme and affect potency, chemical stability, selectivity, and PK properties of the inhibitors. Optimized analogues are extremely potent with subnanomolar K(i)'s, are chemically stable, show very little potency decrease in the presence of plasma, and exhibit more than 1,000-fold selectivity against related peptidases. The best compounds also possess good PK and are efficacious in lowering blood glucose in an oral glucose tolerance test in ZDF rats.
Assuntos
Fármacos Antiobesidade/síntese química , Dipeptidil Peptidase 4/metabolismo , Hipoglicemiantes/síntese química , Nitrilas/síntese química , Inibidores de Proteases/síntese química , Pirrolidinas/síntese química , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Glicemia/análise , Domínio Catalítico , Cristalografia por Raios X , Estabilidade de Medicamentos , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Modelos Moleculares , Nitrilas/farmacocinética , Nitrilas/farmacologia , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/farmacologia , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.
Assuntos
Inibidores de Adenosina Desaminase , Inibidores da Dipeptidil Peptidase IV , Glicoproteínas/antagonistas & inibidores , Hipoglicemiantes/síntese química , Piridinas/síntese química , Pirrolidinas/síntese química , Adenosina Desaminase/química , Administração Oral , Animais , Sítios de Ligação , Células CACO-2 , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/química , Cães , Feminino , Intolerância à Glucose/tratamento farmacológico , Glicoproteínas/química , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Macaca fascicularis , Modelos Moleculares , Estrutura Molecular , Piridinas/farmacocinética , Piridinas/farmacologia , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Glucagon-like peptide-1 (GLP-1 (7-36) amide) is a gut hormone released from L-cells in the small intestine in response to the ingestion of nutrients and enhances the glucose-dependent secretion of insulin from pancreatic beta-cells. In type 2 diabetic patients, the continuous infusion of GLP-1 (7-36) amide decreases plasma glucose and hemoglobin A1c concentrations and improves beta-cell function. Hormone action is rapidly terminated by the N-terminal cleavage of GLP-1 at Ala2 by the aminopeptidase, dipeptidyl peptidase IV (DPPIV). The short in vivo half-life of GLP-1 (< 3 min) poses challenges to the development of exogenous GLP-1-based therapy. The inhibition of endogenous GLP-1 degradation by reducing DPPIV activity is an alternative strategy for improving the incretin action of GLP-1 in vivo. This review summarizes recent advances in the design of potent and selective small molecule inhibitors of DPPIV and the potential challenges to the development of DPPIV inhibitors for the treatment of impaired glucose tolerance and type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/fisiologia , Intolerância à Glucose/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Inibidores de Proteases/uso terapêutico , Animais , Diabetes Mellitus Tipo 2/complicações , Dipeptidil Peptidase 4/química , Desenho de Fármacos , Intolerância à Glucose/etiologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Pirrolidinas/uso terapêuticoAssuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV , Hipoglicemiantes/uso terapêutico , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/enzimologia , Dipeptidil Peptidase 4 , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Secreção de Insulina , Relação Estrutura-AtividadeRESUMO
Dipeptidyl peptidase IV (DPP-IV) belongs to a family of serine peptidases, and due to its indirect regulatory role in plasma glucose modulation, DPP-IV has become an attractive pharmaceutical target for diabetes therapy. DPP-IV inactivates the glucagon-like peptide (GLP-1) and several other naturally produced bioactive peptides that contain preferentially a proline or alanine residue in the second amino acid sequence position by cleaving the N-terminal dipeptide. To elucidate the details of the active site for structure-based drug design, we crystallized a natural source preparation of DPP-IV isolated from rat kidney and determined its three-dimensional structure using X-ray diffraction techniques. With a high degree of similarity to structures of human DPP-IV, the active site architecture provides important details for the design of inhibitory compounds, and structures of inhibitor-protein complexes offer detailed insight into three-dimensional structure-activity relationships that include a conformational change of Tyr548. Such accommodation is exemplified by the response to chemical substitution on 2-cyanopyrrolidine inhibitors at the 5 position, which conveys inhibitory selectivity for DPP-IV over closely related homologues. A similar conformational change is also observed in the complex with an unrelated synthetic inhibitor containing a xanthine core that is also selective for DPP-IV. These results suggest the conformational flexibility of Tyr548 is unique among protein family members and may be utilized in drug design to achieve peptidase selectivity.
Assuntos
Dipeptidases/antagonistas & inibidores , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Rim/enzimologia , Animais , Sítios de Ligação , Cristalização , Dimerização , Dipeptidases/química , Dipeptidases/metabolismo , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/isolamento & purificação , Peptídeo 1 Semelhante ao Glucagon/química , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Cinética , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Ratos , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Tirosina/química , Difração de Raios XRESUMO
The synthesis and biological activities of rapamycin (I) analogs modified at the C-40 position are reported. Emphasis placed on compounds that potentially have an improved safety profile on account of their shorter in vivo half-life when compared with rapamycin.
Assuntos
Antirreumáticos/química , Antirreumáticos/farmacocinética , Artrite Reumatoide/metabolismo , Sirolimo/análogos & derivados , Animais , Antirreumáticos/toxicidade , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Masculino , Radiografia , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-DawleyRESUMO
A novel series of antimicrobials of the oxazolidinone class is disclosed. These compounds are characterized relative to previously described analogues by a 'halostilbene-derived' pharmacophore and demonstrate enhanced antimicrobial activity against key Gram-positive pathogens when compared to Linezolid.