RESUMO
Induction of IFNα in the upper airways via activation of TLR7 represents a novel immunomodulatory approach to the treatment of allergic asthma. Exploration of 8-oxoadenine derivatives bearing saturated oxygen or nitrogen heterocycles in the N-9 substituent has revealed a remarkable selective enhancement in IFNα inducing potency in the nitrogen series. Further potency enhancement was achieved with the novel (S)-pentyloxy substitution at C-2 leading to the selection of GSK2245035 (32) as an intranasal development candidate. In human cell cultures, compound 32 resulted in suppression of Th2 cytokine responses to allergens, while in vivo intranasal administration at very low doses led to local upregulation of TLR7-mediated cytokines (IP-10). Target engagement was confirmed in humans following single intranasal doses of 32 of ≥20 ng, and reproducible pharmacological response was demonstrated following repeat intranasal dosing at weekly intervals.
Assuntos
Adenina/análogos & derivados , Asma/tratamento farmacológico , Descoberta de Drogas , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Receptor 7 Toll-Like/agonistas , Adenina/administração & dosagem , Adenina/química , Adenina/farmacologia , Administração Intranasal , Asma/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Piperidinas/química , Relação Estrutura-AtividadeRESUMO
There is a high demand for potent, selective, and brain-penetrant small molecule inhibitors of leucine-rich repeat kinase 2 (LRRK2) to test whether inhibition of LRRK2 kinase activity is a potentially viable treatment option for Parkinson's disease patients. Herein we disclose the use of property and structure-based drug design for the optimization of highly ligand efficient aminopyrimidine lead compounds. High throughput in vivo rodent cassette pharmacokinetic studies enabled rapid validation of in vitro-in vivo correlations. Guided by this data, optimal design parameters were established. Effective incorporation of these guidelines into our molecular design process resulted in the discovery of small molecule inhibitors such as GNE-7915 (18) and 19, which possess an ideal balance of LRRK2 cellular potency, broad kinase selectivity, metabolic stability, and brain penetration across multiple species. Advancement of GNE-7915 into rodent and higher species toxicity studies enabled risk assessment for early development.
Assuntos
Encéfalo/metabolismo , Morfolinas/farmacologia , Doença de Parkinson/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Animais , Desenho de Fármacos , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Macaca fascicularis , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Morfolinas/síntese química , Morfolinas/farmacocinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos , Bibliotecas de Moléculas Pequenas , Distribuição TecidualRESUMO
Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-α production from isolated human peripheral blood mononuclear cells.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Compostos Heterocíclicos/química , Inibidores de Fosfodiesterase/química , Pirazóis/química , Piridinas/química , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Humanos , Modelos Químicos , Modelos Moleculares , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Estrutura Terciária de Proteína , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
[reaction: see text] In this, the second of two Letters, the optimization of the pyrrolidine-5,5-trans-lactam template (exemplified by 1a) as a mechanism-based inhibitor of hepatitis C NS3/4A protease is described. "Right Box" analysis of cassette dosing screening pharmacokinetic data was used to rapidly categorize the compounds. GW0014 (compound 4d) emerged as the compound displaying an optimal balance of biochemical and replicon potency, along with low i.v. clearance in the dog.
Assuntos
Lactamas/química , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Pirrolidinas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Concentração Inibidora 50 , Estrutura Molecular , Inibidores de Proteases/química , Proteínas não Estruturais Virais/metabolismoRESUMO
A series of chiral, (S)-proline-alpha-methylpyrrolidine-5,5-trans-lactam serine protease inhibitors has been developed as antivirals of human cytomegalovirus (HCMV). The SAR of the functionality on the proline nitrogen has shown that derivatives of para-substituted phenyl ureas > para-substituted phenyl sulfonamides > para-substituted phenyl carboxamide for activity against HCMV deltaAla protease, producing para-substituted phenyl ureas with single figure nM potency (K(i)) against the viral enzyme. The SAR of the functionality on the lactam nitrogen has defined the steric and electronic requirements for high human plasma stability while retaining good activity against HCMV protease. The combination of high potency against HCMV deltaAla protease and high human plasma stability has produced compounds with significant in vitro antiviral activity against human cytomegalovirus with the 6-hydroxymethyl benzothiazole derivative 72 being equivalent in potency to ganciclovir. The parent benzothiazole 56 had good pharmacokinetics in dogs with 29% bioavailability and good brain and ocular penetration in guinea pigs.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/enzimologia , Lactamas/síntese química , Lactamas/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Serina Endopeptidases/metabolismo , Animais , Antivirais/sangue , Disponibilidade Biológica , Encéfalo/metabolismo , Células Cultivadas , Cães , Desenho de Fármacos , Ensaio de Imunoadsorção Enzimática , Olho/metabolismo , Ganciclovir/farmacologia , Cobaias , Meia-Vida , Humanos , Indicadores e Reagentes , Cinética , Espectrometria de Massas , Modelos Moleculares , Inibidores de Proteases/sangue , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
The pyrrolidine-5,5-trans-lactam template was used to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease displaying potent activity in the replicon cell-based assay. The activity of this series is not dependent upon its chemical reactivity and molecules have been synthesised which combine enhanced biochemical potency with improved plasma stability. Promising initial pharmacokinetic data indicating the potential for further optimisation of this series into low molecular weight, drug-like inhibitors is presented.
Assuntos
Desenho de Fármacos , Hepacivirus/enzimologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Cristalografia por Raios X , Cães , Estabilidade de Medicamentos , Hepacivirus/efeitos dos fármacos , Humanos , Injeções Intravenosas , Lactamas/síntese química , Lactamas/farmacocinética , Lactamas/farmacologia , Modelos Biológicos , Estrutura Molecular , Inibidores de Proteases/farmacocinética , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Ratos , Proteínas não Estruturais Virais/metabolismoRESUMO
Using the pyrrolidine-5,5-trans-lactam template, we have designed small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. Compound 2b, with a spiro-cyclobutyl P1 substituent and an isopropyl carbonyl substituent at the lactam nitrogen, has an IC(50) value in the replicon cell-based assay of 3 microM.