RESUMO
To discover the best-in-class Bruton's Tyrosine Kinase (BTK) inhibitors, for th treatment of autoimmune disorders like cancer (B-Cell Lymphoma (BCL)) and rheumatoid arthritis (RA), in the present investigation, novel structural optimizations were carried out. Introduction of novel bicyclic amine linkers and aromatic backbone led to series of compounds 9a-h and 14a-u. Compound 14b was found to be potent, orally bioavailable, selective and irreversible BTK inhibitor. In vitro, 14b showed IC50 of 1.0 nM and 0.8 nM, in BTK and TMD8 assays, respectively. In vivo,14b displayed robust efficacy in collagen-induced arthritis (CIA) and TMD8 xenograft models, which could be correlated with its improved oral bioavailability. In the repeated dose acute toxicity study, 14b showed no adverse changes, indicating that the BTK inhibitor 14b could be viable therapeutic option for the treatment of autoimmune disorders.
Assuntos
Artrite Experimental , Artrite Reumatoide , Animais , Humanos , Tirosina Quinase da Agamaglobulinemia , Inibidores de Proteínas Quinases/química , Aminas/farmacologia , Aminas/uso terapêutico , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológicoRESUMO
In an effort to develop safe and efficacious compounds for the treatment of metabolic disorders, novel thiophene substituted oxazole containing α-alkoxy-phenylpropanoic acid derivatives are designed as highly potent PPARα/γ dual agonists. These compounds were found to be efficacious at picomolar concentrations. Lead compound 18d has emerged as very potent PPARα/γ dual agonist demonstrating potent antidiabetic and lipid lowering activity at a very low dose and did not exhibit any significant signs of toxicity in rodents.
Assuntos
PPAR alfa/agonistas , PPAR gama/agonistas , Fenilpropionatos/síntese química , Fenilpropionatos/farmacologia , Administração Oral , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Oxazóis/química , Fenilpropionatos/química , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , Rosiglitazona , Tiazolidinedionas/síntese química , Tiazolidinedionas/química , Tiazolidinedionas/farmacologia , Tiofenos/químicaRESUMO
A series of novel 1,3-dioxane-2-carboxylic acid derivatives containing alkyl chain tether and substituted phenyl group as a lipophilic tail have been prepared as agonists of PPARalpha and gamma. c-5-[6-(4-Methanesulfonyloxyphenyl)hexyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid 13c exhibited potent hypoglycemic and lipid lowering activity with high oral bioavailability in animal models.
Assuntos
Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacocinética , Dioxanos/síntese química , Hipoglicemiantes/síntese química , Hipolipemiantes/síntese química , Mesilatos/síntese química , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dioxanos/farmacocinética , Humanos , Lipídeos/química , Mesilatos/farmacocinética , Camundongos , Modelos Químicos , PPAR alfa/metabolismo , PPAR gama/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Ratos , Ratos Wistar , Ativação TranscricionalRESUMO
Design, synthesis and conformational analysis of few imidazole and oxazole as bioisosters of 4S-(-)-3-(4-chlorophenyl)-N-methyl-N'-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-caboxamidine (SLV-319) 2 is reported. Computer assisted conformational analysis gave a direct clue for the loss of CB1 antagonistic activity of the ligands without a fine docking simulation for the homology model.
Assuntos
Imidazóis/química , Imidazóis/farmacologia , Modelos Moleculares , Oxazóis/química , Oxazóis/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Sulfonamidas/química , Sulfonamidas/farmacologia , Animais , Técnicas de Química Combinatória , Cricetinae , Cricetulus , Desenho de Fármacos , Humanos , Imidazóis/síntese química , Estrutura Molecular , Oxazóis/síntese química , Pirazóis/síntese química , Relação Estrutura-Atividade , Sulfonamidas/síntese químicaRESUMO
A number of analogues of diaryl dihydropyrazole-3-carboxamides have been synthesized. Their activities were evaluated for appetite suppression and body weight reduction in animal models. Depending on the chemical modification of the selected dihydropyrazole scaffold, the lead compounds--the bisulfate salt of (+/-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 26 and the bisulfate salt of (-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 30--showed significant body weight reduction in vivo, which is attributed to their CB1 antagonistic activity and exhibited a favorable pharmacokinetic profile. The molecular modeling studies also showed interactions of two isomers of (+/-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 9 with CB1 receptor in the homology model similar to those of N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (rimonabant) 1 and 4S-(-)-3-(4-chlorophenyl)-N-methyl-N'-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (SLV-319) 2.