RESUMO
A rational fluorine scan based on co-crystal structures was explored to increase the potency of a series of selective BTK inhibitors. While fluorine substitution on a saturated bicyclic ring system yields no apparent benefit, the same operation on an unsaturated bicyclic ring can increase HWB activity by up to 40-fold. Comparison of co-crystal structures of parent molecules and fluorinated counterparts revealed the importance of placing fluorine at the optimal position to achieve favorable interactions with protein side chains.
Assuntos
Flúor/química , Flúor/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/metabolismo , Tirosina Quinase da Agamaglobulinemia , Cristalografia por Raios X , Humanos , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012 , 341 , 90 ), which was selected for advanced preclinical characterization based on its favorable properties.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Isoquinolinas/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Isoquinolinas/química , Isoquinolinas/metabolismo , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/metabolismoRESUMO
The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.
Assuntos
Descoberta de Drogas/métodos , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Piridonas/farmacologia , Piridonas/farmacocinética , Pirimidinas/farmacologia , Pirimidinas/farmacocinética , Administração Oral , Artrite Reumatoide/tratamento farmacológico , Disponibilidade Biológica , Linhagem Celular , Ensaios Clínicos como Assunto , Humanos , Proteína Quinase 14 Ativada por Mitógeno/química , Modelos Moleculares , Conformação Proteica , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Piridonas/administração & dosagem , Piridonas/química , Pirimidinas/administração & dosagem , Pirimidinas/química , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
RG7128 is a di-ester prodrug of a cytidine analog for the treatment of hepatitis C virus (HCV) infection. The structures of nine low level impurities (0.05-0.10%) in RG7128 drug substance were elucidated. The majority of the impurities were formed during the synthesis of the prodrug from the parent drug. Structural elucidations of the impurities were achieved either by enrichment of the impurities using preparative chromatography followed by spectroscopic techniques or by confirmation with a reference sample. Heart-cut and recycle chromatographic techniques were applied to purify closely eluting isomers of RG7128.
Assuntos
Antivirais/análise , Desoxicitidina/análogos & derivados , Contaminação de Medicamentos , Hepatite C/tratamento farmacológico , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Cromatografia Líquida de Alta Pressão , Desoxicitidina/análise , Ésteres/análise , Espectroscopia de Ressonância Magnética , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are part of the preferred treatment regimens for individuals infected with HIV. These NNRTI-based regimens are efficacious, but the most popular NNRTIs have a low genetic barrier to resistance and have been associated with adverse events. There is therefore still a need for efficacious antiviral medicines that facilitate patient adherence and allow durable suppression of viral replication. As part of an extensive program targeted toward the discovery of NNRTIs that have favorable pharmacokinetic properties, good potency against NNRTI-resistant viruses, and a high genetic barrier to drug resistance, we focused on the optimization of a series of diaryl ether NNRTIs. In the course of this effort, we employed molecular modeling to design a new set of NNRTIs that that are active against wild-type HIV and key NNRTI-resistant mutant viruses. The structure-activity relationships observed in this series of compounds provide insight into the structural features required for NNRTIs that inhibit the replication of a wide range of mutant viruses. Selected compounds have promising pharmacokinetic profiles.
Assuntos
Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/química , Éteres Fenílicos/química , Éteres Fenílicos/farmacologia , Inibidores da Transcriptase Reversa/química , Animais , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Simulação por Computador , Cães , Desenho de Fármacos , Farmacorresistência Viral/genética , HIV/genética , Transcriptase Reversa do HIV/antagonistas & inibidores , Concentração Inibidora 50 , Modelos Moleculares , Mutação , Éteres Fenílicos/farmacocinética , Ratos , Inibidores da Transcriptase Reversa/farmacocinética , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-AtividadeRESUMO
The nucleoside analog R1479 is a potent and highly selective inhibitor of NS5b-directed hepatitis C virus (HCV) RNA polymerase in vitro. Because of its limited permeability, lipophilic prodrugs of R1479 were screened. Selection of the prodrug involved optimization of solubility, permeability, and stability parameters. R1626 has dissociation constant, intrinsic solubility, log partition coefficient (n-octanol water), and Caco-2 permeability of 3.62, 0.19 mg/mL, 2.45, and 14.95 x 10(-6) cm/s, respectively. The hydrolysis of the prodrug is significantly faster in the Caco-2 experiments than in hydrolytic experiments, suggesting that the hydrolysis is catalyzed by enzymes in the cellular membrane. Using GastroPlus, the physical properties of R1626 successfully predict the dose dependence of the pharmacokinetics in humans previously studied. The program predicts that if the particle size of R1626 is less than 25 microm, it will be well absorbed. Prodrugs with a solubility of greater than 100 microg/mL and permeability in the Caco-2 assay greater than 3 x 10(-6) cm/s are expected to achieve a high fraction absorbed.
Assuntos
Antivirais/farmacocinética , Citidina/análogos & derivados , Nucleosídeos/farmacocinética , Pró-Fármacos/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Citidina/farmacocinética , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Hepacivirus/efeitos dos fármacos , Humanos , Hidrólise , Nucleosídeos/administração & dosagem , Tamanho da Partícula , Permeabilidade , Pró-Fármacos/administração & dosagem , Solubilidade , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
A series of 4'-substituted ribonucleoside derivatives has been prepared and evaluated for inhibition of hepatitis C virus (HCV) RNA replication in cell culture. The most potent and non-cytotoxic derivative was compound 28 (4'-azidocytidine, R1479) with an IC(50) of 1.28 microM in the HCV replicon system. The triphosphate of compound 28 was prepared and shown to be an inhibitor of RNA synthesis mediated by NS5B (IC(50)=320 nM), the RNA polymerase encoded by HCV. Data on related analogues have been used to generate some preliminary requirements for activity within this series of nucleosides.
Assuntos
Antivirais/química , Química Farmacêutica/métodos , Citidina/análogos & derivados , Hepacivirus/genética , Ribonucleosídeos/química , Replicação Viral/efeitos dos fármacos , Citidina/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Nucleosídeos/química , RNA/química , UridinaRESUMO
Hepatitis C virus (HCV) polymerase activity is essential for HCV replication. Targeted screening of nucleoside analogs identified R1479 (4'-azidocytidine) as a specific inhibitor of HCV replication in the HCV subgenomic replicon system (IC(50) = 1.28 microM) with similar potency compared with 2'-C-methylcytidine (IC(50) = 1.13 microM). R1479 showed no effect on cell viability or proliferation of HCV replicon or Huh-7 cells at concentrations up to 2 mM. HCV replicon RNA could be fully cleared from replicon cells after prolonged incubation with R1479. The corresponding 5'-triphosphate derivative (R1479-TP) is a potent inhibitor of native HCV replicase isolated from replicon cells and of recombinant HCV polymerase (NS5B)-mediated RNA synthesis activity. R1479-TP inhibited RNA synthesis as a CTP-competitive inhibitor with a K(i) of 40 nM. On an HCV RNA-derived template substrate (complementary internal ribosome entry site), R1479-TP showed similar potency of NS5B inhibition compared with 3'-dCTP. R1479-TP was incorporated into nascent RNA by HCV polymerase and reduced further elongation with similar efficiency compared with 3'-dCTP under the reaction conditions. The S282T point mutation in the coding sequence of NS5B confers resistance to inhibition by 2'-C-MeATP and other 2'-methyl-nucleotides. In contrast, the S282T mutation did not confer cross-resistance to R1479.
Assuntos
Antivirais/farmacologia , Citidina/análogos & derivados , Hepacivirus/efeitos dos fármacos , RNA Viral/biossíntese , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Linhagem Celular , Citidina/farmacologia , Hepacivirus/fisiologia , HumanosRESUMO
A novel series of TNF inhibitors was identified based on the screening of existing MMP inhibitor libraries. Further SAR optimization led to the discovery of a novel lead compound. Its synthesis, efficacy in experimental animal models, and pharmacokinetic data are discussed.