RESUMO
Efforts to improve the genotype 1a potency and pharmacokinetics of earlier naphthyridine-based HCV NS5A inhibitors resulted in the discovery of a novel series of pyrido[2,3-d]pyrimidine compounds, which displayed potent inhibition of HCV genotypes 1a and 1b in the replicon assay. SAR in this system revealed that the introduction of amides bearing an additional 'E' ring provided compounds with improved potency and pharmacokinetics. Introduction of a chiral center on the amide portion resulted in the observation of a stereochemical dependence for replicon potency and provided a site for the attachment of functional groups useful for improving the solubility of the series. Compound 21 was selected for administration in an HCV-infected chimpanzee. Observation of a robust viral load decline provided positive proof of concept for inhibition of HCV replication in vivo for the compound series.
Assuntos
Pirimidinas/química , Pirimidinas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Descoberta de Drogas , Humanos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismoRESUMO
The synthesis of several pyrido[2,3-d]pyrimidine and pyrimido[4,5-d]pyrimidine analogs is described with one such analog possessing subnanomolar potency in both genotype 1a and 1b cell culture HCV replicon assays.
Assuntos
Antivirais/síntese química , Hepacivirus/efeitos dos fármacos , Pirimidinas/síntese química , RNA Viral/antagonistas & inibidores , Antivirais/farmacologia , Linhagem Celular Tumoral , Genótipo , Hepacivirus/fisiologia , Humanos , Pirimidinas/farmacologia , RNA Viral/biossíntese , Replicon/efeitos dos fármacos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
The antiapoptotic proteins Bcl-x(L) and Bcl-2 play key roles in the maintenance of normal cellular homeostasis. However, their overexpression can lead to oncogenic transformation and is responsible for drug resistance in certain types of cancer. This makes Bcl-x(L) and Bcl-2 attractive targets for the development of potential anticancer agents. Here we describe the structure-based discovery of a potent Bcl-x(L) inhibitor directed at a hydrophobic groove on the surface of the protein. This groove represents the binding site for BH3 peptides from proapoptotic Bcl-2 family members such as Bak and Bad. Application of NMR-based screening yielded an initial biaryl acid with an affinity (K(d)) of approximately 300 microM for the protein. Following the classical "SAR by NMR" approach, a second-site ligand was identified that bound proximal to the first-site ligand in the hydrophobic groove. From NMR-based structural studies and parallel synthesis, a potent ligand was obtained, which binds to Bcl-x(L) with an inhibition constant (K(i)) of 36 +/- 2 nM.
Assuntos
Compostos de Anilina/síntese química , Modelos Moleculares , Sulfonamidas/síntese química , Proteína bcl-X/antagonistas & inibidores , Compostos de Anilina/química , Sítios de Ligação , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Espectroscopia de Ressonância Magnética , Ligação Proteica , Solubilidade , Relação Estrutura-Atividade , Sulfonamidas/química , Proteína bcl-X/químicaRESUMO
Efforts to further elucidate structure-activity relationships (SAR) within our previously disclosed series of beta-quaternary amino acid linked l-cis-4,5-methanoprolinenitrile dipeptidyl peptidase IV (DPP-IV) inhibitors led to the investigation of vinyl substitution at the beta-position of alpha-cycloalkyl-substituted glycines. Despite poor systemic exposure, vinyl-substituted compounds showed extended duration of action in acute rat ex vivo plasma DPP-IV inhibition models. Oxygenated putative metabolites were prepared and were shown to exhibit the potency and extended duration of action of their precursors in efficacy models measuring glucose clearance in Zucker(fa/fa) rats. Extension of this approach to adamantylglycine-derived inhibitors led to the discovery of highly potent inhibitors, including hydroxyadamantyl compound BMS-477118 (saxagliptin), a highly efficacious, stable, and long-acting DPP-IV inhibitor, which is currently undergoing clinical trials for treatment of type 2 diabetes.
Assuntos
Adamantano/análogos & derivados , Adamantano/síntese química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/síntese química , Dipeptidil Peptidase 4/metabolismo , Glicina/análogos & derivados , Glicina/síntese química , Hipoglicemiantes/síntese química , Inibidores de Proteases/síntese química , Adamantano/farmacologia , Animais , Disponibilidade Biológica , Glicemia/análise , Diabetes Mellitus Tipo 2/fisiopatologia , Dipeptídeos/farmacologia , Teste de Tolerância a Glucose , Glicina/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Técnicas In Vitro , Insulina/sangue , Masculino , Camundongos , Camundongos Obesos , Microssomos Hepáticos/metabolismo , Nitrilas/síntese química , Nitrilas/farmacologia , Prolina/análogos & derivados , Prolina/síntese química , Prolina/farmacologia , Inibidores de Proteases/farmacologia , Ratos , Ratos Zucker , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of methanoprolinenitrile-containing dipeptide mimetics were synthesized and assayed as inhibitors of the N-terminal sequence-specific serine protease dipeptidyl peptidase IV (DPP-IV). The catalytic action of DPP-IV is the principle means of degradation of glucagon-like peptide-1, a key mediator of glucose-stimulated insulin secretion, and DPP-IV inhibition shows clinical benefit as a novel mechanism for treatment of type 2 diabetes. However, many of the reversible inhibitors to date suffer from chemical instability stemming from an amine to nitrile intramolecular cyclization. Installation of a cyclopropyl moiety at either the 3,4- or 4,5-position of traditional 2-cyanopyrrolidide proline mimetics led to compounds with potent inhibitory activity against the enzyme. Additionally, cis-4,5-methanoprolinenitriles with beta-branching in the N-terminal amino acid provided enhanced chemical stability and high inhibitory potency. This class of inhibitors also exhibited the ability to suppress prandial glucose elevations after an oral glucose challenge in male Zucker rats.
Assuntos
Ciclopropanos/síntese química , Dipeptidil Peptidase 4/metabolismo , Inibidores Enzimáticos/síntese química , Nitrilas/síntese química , Prolina/análogos & derivados , Prolina/síntese química , Animais , Simulação por Computador , Cristalografia por Raios X , Ciclopropanos/química , Ciclopropanos/farmacologia , Dipeptídeos/química , Dipeptidil Peptidase 4/química , Estabilidade de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Masculino , Modelos Moleculares , Conformação Molecular , Mimetismo Molecular , Nitrilas/química , Nitrilas/farmacologia , Prolina/química , Prolina/farmacologia , Ratos , Ratos Zucker , SoluçõesRESUMO
Pharmacokinetic studies in cynomolgus monkeys with a novel prototype selective androgen receptor modulator revealed trace amounts of an aniline fragment released through hydrolytic metabolism. This aniline fragment was determined to be mutagenic in an Ames assay. Subsequent concurrent optimization for target activity and avoidance of mutagenicity led to the identification of a pharmacologically superior clinical candidate without mutagenic potential.
Assuntos
Antagonistas de Androgênios/química , Antagonistas de Androgênios/síntese química , Química Farmacêutica/métodos , Hidantoínas/química , Hidantoínas/síntese química , Receptores Androgênicos/metabolismo , Antagonistas de Androgênios/farmacologia , Animais , Desenho de Fármacos , Escherichia coli/metabolismo , Genes Reporter , Cinética , Macaca fascicularis , Modelos Químicos , Conformação Molecular , Mutagênese , Mutagênicos , Relação Estrutura-AtividadeRESUMO
A series of non-nucleoside HCV NS5B polymerase inhibitors based on the N-1-benzyl or N-1-[3-methylbutyl]-4-hydroxy-1,8-naphthyridon-3-yl benzothiadiazine core substituted in the D-ring aromatic moiety have been prepared and evaluated. Aromatic substituents extending from position 7 of the D-ring exhibited excellent potency against both genotypes 1a and 1b.
Assuntos
Benzotiadiazinas/farmacologia , Inibidores Enzimáticos/farmacologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Benzotiadiazinas/síntese química , Inibidores Enzimáticos/síntese química , Genótipo , Hidrocarbonetos Aromáticos/química , Concentração Inibidora 50 , Naftiridinas/química , Relação Estrutura-AtividadeRESUMO
The HIV protease inhibitor ABT-378 (Lopinavir) has a 2,6-dimethylphenoxyacetyl group in the P-2' position. Analogues in which this group is replaced with various substituted phenyl or heteroaryl groups were synthesized and the structure-activity relationships explored.
Assuntos
Inibidores da Protease de HIV/síntese química , Pirimidinonas/síntese química , Linhagem Celular , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Humanos , Lopinavir , Pirimidinonas/química , Pirimidinonas/farmacologia , Relação Estrutura-AtividadeRESUMO
The HIV protease inhibitor Lopinavir has a pseudosymmetric core unit incorporating benzyl groups at both P-1, P-1' positions. A series of analogues incorporating non-aromatic side chains at the P-1 position were synthesized and the structure-activity relationships explored.
Assuntos
Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/farmacologia , Linhagem Celular , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Lopinavir , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
The HIV protease inhibitor ABT-378 (lopinavir) has a six-member cyclic urea in the P-2 position. A series of analogues in which the six-member cyclic urea is replaced by various heterocycles was synthesized and the structure-activity relationships explored.