RESUMO
RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Complexo de Proteínas Formadoras de Poros Nucleares/antagonistas & inibidores , Pirazóis/síntese química , Pirazóis/farmacologia , Proteínas de Ligação a RNA/antagonistas & inibidores , Animais , Disponibilidade Biológica , Linhagem Celular , Doença Crônica , Desenho de Fármacos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Inibidores Enzimáticos/farmacocinética , Haplorrinos , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Esclerose Múltipla/tratamento farmacológico , Pirazóis/farmacocinética , Ratos , Retinose Pigmentar/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Lp-PLA2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA2. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA2 inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.
Assuntos
Inibidores Enzimáticos/farmacologia , Lactamas/farmacologia , 1-Alquil-2-acetilglicerofosfocolina Esterase , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Lactamas/administração & dosagem , Lactamas/síntese química , Lactamas/química , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.
Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Pirazóis/farmacologia , Tiazóis/farmacologia , 1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Sítios de Ligação/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaRESUMO
We report the design and synthesis of equipotent PPARalpha/gamma dual agonists starting from selective PPAR alpha agonist 1. In vivo data for 7 in the Zucker fa/fa rat are presented.
Assuntos
PPAR alfa/agonistas , PPAR gama/agonistas , Pirazóis/síntese química , Animais , Técnicas de Química Combinatória , Desenho de Fármacos , Estrutura Molecular , Isoformas de Proteínas , Pirazóis/química , Pirazóis/toxicidade , Ratos , Ratos Zucker , Relação Estrutura-AtividadeRESUMO
We describe the discovery of novel potent inhibitors of 2,3-oxidosqualene:lanosterol cyclase inhibitors (OSCi) from a focused pharmacophore-based screen. Optimization of the most tractable hits gave a series of compounds showing inhibition of cholesterol biosynthesis at 2mg/kg in the rat with distinct pharmacokinetic profiles. Two compounds were selected for toxicological study in the rat for 21 days in order to test the hypothesis that low systemic exposure could be used as a strategy to avoid the ocular side effects previously described with OSCi. We demonstrate that for this series of inhibitors, a reduction of systemic exposure is not sufficient to circumvent cataract liabilities.
Assuntos
Catarata/enzimologia , Dislipidemias/enzimologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Olho/efeitos dos fármacos , Transferases Intramoleculares/antagonistas & inibidores , Animais , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/síntese química , Anticolesterolemiantes/farmacocinética , Catarata/induzido quimicamente , Catarata/tratamento farmacológico , Linhagem Celular Tumoral , Dislipidemias/induzido quimicamente , Inibidores Enzimáticos/efeitos adversos , Olho/metabolismo , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Oxazóis/farmacocinética , Oxazóis/uso terapêutico , Piperazinas/efeitos adversos , Piperazinas/síntese química , Piperazinas/farmacocinética , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Ratos , Ratos Sprague-DawleyRESUMO
Starting from the structure of 5, a two-step strategy was applied to identify a new generation of trifluoromethane sulfonamides as potent PPARalpha agonists. Synthesis, in vitro and in vivo evaluation of the most potent compound are reported.
Assuntos
PPAR alfa/agonistas , Sulfonamidas/química , Sulfonamidas/farmacologia , Animais , Linhagem Celular , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Sulfonamidas/síntese químicaRESUMO
The peroxisome proliferator activated receptors PPARalpha, PPARgamma, and PPARdelta are ligand-activated transcription factors that play a key role in lipid homeostasis. The fibrates raise circulating levels of high-density lipoprotein cholesterol and lower levels of triglycerides in part through their activity as PPARalpha agonists; however, the low potency and restricted selectivity of the fibrates may limit their efficacy, and it would be desirable to develop more potent and selective PPARalpha agonists. Modification of the selective PPARdelta agonist 1 (GW501516) so as to incorporate the 2-aryl-2-methylpropionic acid group of the fibrates led to a marked shift in potency and selectivity toward PPARalpha agonism. Optimization of the series gave 25a, which shows EC50 = 4 nM on PPARalpha and at least 500-fold selectivity versus PPARdelta and PPARgamma. Compound 25a (GW590735) has been progressed to clinical trials for the treatment of diseases of lipid imbalance.