RESUMO
The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. In our preceding paper, we have reported on a series of novel and orally active N-hydroxy-alpha-phenylsulfonylacetamide derivatives. However, these compounds had two drawbacks (moderate selectivity and chirality issues). To circumvent these two problems, a series of novel and orally active N-substituted 4-benzenesulfonylpiperidine-4-carboxylic acid hydroxyamide derivatives have been synthesized. The present paper deals with the synthesis and SAR of these compounds. Among the several compounds synthesized, derivative 55 turned out to be a potent, selective, and an orally active MMP inhibitor in the clinically relevant advanced rabbit osteoarthritis model. Detailed pharmacokinetics and metabolism data are described.
Assuntos
Ácidos Hidroxâmicos/síntese química , Inibidores de Metaloproteinases de Matriz , Osteoartrite/tratamento farmacológico , Piperidinas/síntese química , Inibidores de Proteases/síntese química , Sulfonas/síntese química , Proteínas ADAM , Proteína ADAM17 , Administração Oral , Animais , Sítios de Ligação , Bioensaio , Cartilagem/efeitos dos fármacos , Cartilagem/enzimologia , Bovinos , Cristalografia por Raios X , Diálise , Cães , Haplorrinos , Humanos , Ácidos Hidroxâmicos/farmacocinética , Ácidos Hidroxâmicos/farmacologia , Masculino , Metaloproteinase 13 da Matriz , Metaloproteinases da Matriz/química , Metaloendopeptidases/antagonistas & inibidores , Camundongos , Modelos Moleculares , Piperidinas/farmacocinética , Piperidinas/farmacologia , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/farmacologia , Coelhos , Ratos , Relação Estrutura-Atividade , Sulfonas/farmacocinética , Sulfonas/farmacologiaRESUMO
Voltage-gated K(+) channels are potential drug targets for an increasing number of disease indications. Searching for compounds that modulate K(+) channel activities by high-throughput screening (HTS) is becoming a standard approach in the drug discovery effort. Here the authors report an improved fluorometric imaging plate reader (FLIPR) membrane potential assay for Kv1.3 K(+) channel HTS. They have found that the Chinese hamster ovary (CHO) cells have endogenous membrane electrogenic transporters that contribute to maintaining membrane potential. Blocking the recombinant K(+) channels in the overexpressing CHO cell line hardly changed the membrane potential. Inhibition of the endogenous transporters is essential to achieve the required assay robustness. The authors identified the optimal assay conditions and designed a simple assay format. After an HTS campaign using this assay, various chemical series of Kv1.3 channel blockers have been identified and confirmed by the automated electrophysiological IonWorks assay. The correlation in dose response between FLIPR and IonWorks was established by biophysical modeling and experimental data. After characterization using patch-clamp recording, both use-dependent and use-independent compounds were identified. Some compounds possess nanomolar potency, indicating that the FLIPR assay is effective for successfully identifying K(+) channel blockers as novel drug candidates.
Assuntos
Bioensaio , Ensaios de Triagem em Larga Escala , Canal de Potássio Kv1.3/antagonistas & inibidores , Potenciais da Membrana/fisiologia , Bloqueadores dos Canais de Potássio/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Eletrofisiologia , Fluorometria , Concentração Inibidora 50 , Técnicas de Patch-Clamp , Azida Sódica/farmacologiaRESUMO
Piperidine, pyrrolidine, and azetidine sulfonamides were examined as linkers in designing novel human beta(3) adrenergic receptor (beta(3)-AR) agonists. The azetidine derivative 37, and piperidine derivatives 7, 8, and 13 were found to be potent beta(3)-AR agonists and have good selectivity against beta(1)- and beta(2)-AR.