RESUMO
A series of ß-aminoacyl containing thiazolidine derivatives was synthesized and evaluated for their ability to inhibit DPP-IV. Several thiazolidine derivatives with an acid moiety were found to be potent DPP-IV inhibitors. Among them, compound 2da is the most active in this series with an IC(50) value of 1 nM, and it showed excellent selectivity over DPP-IV related enzymes including DPP-2, DPP-8, and DPP-9. Compound 2da is chemically and metabolically stable, and showed no CYP inhibition, hERG binding or cytotoxicity. Compound 2db, an ester prodrug of 2da, showed good in vivo DPP-IV inhibition after oral administration in rat and dog models.
Assuntos
Inibidores da Dipeptidil Peptidase IV/síntese química , Tiazolidinas/síntese química , Administração Oral , Animais , Cristalografia por Raios X , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Modelos Animais de Doenças , Cães , Ativação Enzimática/efeitos dos fármacos , Concentração Inibidora 50 , Estrutura Molecular , Ratos , Tiazolidinas/química , Tiazolidinas/farmacologiaRESUMO
Compounds with homopiperazine skeleton are designed to find a potent DPP-IV inhibitor without inhibiting CYP. Thus a series of beta-aminoacyl-containing homopiperazine derivatives was synthesized and evaluated. Compounds with acid moiety were found to be potent inhibitors of DPP-IV without inhibiting CYP 3A4. More specifically, compound 7m showed nanomolar activity with no inhibition towards five subtypes of CYPs, was considered as a prototype for further derivatization. Based on its X-ray co-crystal structure with human DPP-IV, we identified compounds 7s and 7t which showed good in vitro activity, no CYP inhibition, and good selectivity.
Assuntos
Química Farmacêutica/métodos , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Piperazinas/química , Sítios de Ligação , Cristalografia por Raios X/métodos , Citocromo P-450 CYP3A/química , Diabetes Mellitus/tratamento farmacológico , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Piperazina , Pirazinas/farmacologia , Fosfato de Sitagliptina , Relação Estrutura-Atividade , Triazóis/farmacologiaRESUMO
A series of pyrazoline derivatives with beta-amino acyl group were synthesized and evaluated for their ability to inhibit dipeptidyl peptidase IV. Several pyrazoline derivatives exhibited submicromolar inhibitory activities against DPP-IV. X-ray co-crystal structure of initial hit compound 1h was determined. Among this series, carboxylic acid substituted pyrazoline derivative 2u was the most active and greatly decreased the inhibitory activity toward CYP3A4 enzyme.
Assuntos
Aminas/química , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Células CACO-2 , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Inibidores da Dipeptidil Peptidase IV/química , Humanos , Concentração Inibidora 50 , Pirazóis/química , Relação Estrutura-AtividadeRESUMO
The histamine H4 receptor (H4R), a member of the G-protein coupled receptor family, has been considered as a potential therapeutic target for treating atopic dermatitis (AD). A large number of H4R antagonists have been disclosed, but no efficient agents controlling both pruritus and inflammation in AD have been developed yet. Here, we have discovered a novel class of orally available H4R antagonists showing strong anti-itching and anti-inflammation activity as well as excellent selectivity against off-targets. A pharmacophore-based virtual screening system constructed in-house successfully identified initial hit compound 9, and the subsequent homology model-guided optimization efficiently led us to discover pyrido[2,3- e]tetrazolo[1,5- a]pyrazine analogue 48 as a novel chemotype of a potent and highly selective H4R antagonist. Importantly, orally administered compound 48 exhibits remarkable efficacy on antipruritus and anti-inflammation with a favorable pharmacokinetic (PK) profile in several mouse models of AD. Thus, these data strongly suggest that our compound 48 is a promising clinical candidate for treatment of AD.
Assuntos
Dermatite Atópica/tratamento farmacológico , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/uso terapêutico , Receptores Histamínicos H4/antagonistas & inibidores , Animais , Disponibilidade Biológica , Simulação por Computador , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Feminino , Antagonistas dos Receptores Histamínicos/farmacocinética , Inflamação/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Modelos Moleculares , Conformação Molecular , Simulação de Acoplamento Molecular , Prurido/tratamento farmacológico , Receptores Histamínicos H4/metabolismo , Relação Estrutura-AtividadeRESUMO
A new synthetic small molecule, compound 1, which induced a neuronal differentiation from mesenchymal stem cells (MSCs) with an excellent efficiency, was identified. Furthermore the differentiated cell by 1 showed the neural electrophysiological and cholinergic neuron properties.
Assuntos
Células-Tronco Mesenquimais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular , Fenômenos Eletrofisiológicos , Perfilação da Expressão Gênica , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/fisiologia , Neurônios/citologia , Neurônios/fisiologia , RatosRESUMO
A series of rhodanine derivatives was synthesized and evaluated for their ability to inhibit PRL-3. Benzylidene rhodanine derivative showed good biological activity, while compound 5e was the most active in this series exhibiting an IC50 value of 0.9 microM in vitro and showed a reduced invasion in cell-based assay.