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1.
Bioorg Med Chem ; 23(4): 779-90, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25596166

RESUMO

We have previously reported a novel series of 3H-imidazo[4,5-c]quinolin-4(5H)-ones with potent dipeptidyl peptidase IV (DPP-4) inhibitory activity. However, these compounds showed poor oral absorption. We attempted in this study esterification of the carboxylic acid moiety to improve the compounds 1-4 plasma concentrations. Our efforts yielded 10h with a 5-methyl-2-oxo-1,3-dioxol-4-yl methyl ester as an S9/plasma-cleavable functionality. Compound 10h showed significantly high oral absorption and potent DPP-4 inhibition in vivo and decreased Zucker fatty rats glucose levels in the oral glucose tolerance test. Optimization of the ester moiety revealed that rapid conversion to the carboxyl form in both liver S9 fractions and serum was important for prodrugs not to be detected in the plasma after oral administration. In particular, lability in the serum was found to be an important characteristic. Through our investigation, we were able to develop a novel efficient synthetic method for construction of 3H-imidazo[4,5-c]quinolin-4(5H)-ones using intramolecular radical cyclization.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Quinolinas/química , Quinolinas/uso terapêutico , Animais , Glicemia/análise , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/metabolismo , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/farmacocinética , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Masculino , Modelos Moleculares , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/uso terapêutico , Quinolinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Ratos Zucker
2.
Bioorg Med Chem ; 20(19): 5864-83, 2012 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-22938786

RESUMO

In recent years, dipeptidyl peptidase IV inhibitors have been noted as valuable agents for treatment of type 2 diabetes. Herein, we report the discovery of a novel potent DPP-4 inhibitor with 3H-imidazo[4,5-c]quinolin-4(5H)-one as skeleton. After efficient optimization of the lead compound 2a at the 7- and 8-positions using a docking study, we found 28 as a novel DPP-4 inhibitor with excellent selectivity against various DPP-4 homologues. Compound 28 showed strong DPP-4 inhibitory activity compared to marketed DPP-4 inhibitors. We also found that a carboxyl group at the 7-position could interact with the residue of Lys554 to form a salt bridge. Additionally, introduction of a carboxyl group to 7-position led to both activity enhancement and reduced risk for hERG channel inhibition and induced phospholipidosis. In our synthesis of compounds with 7-carboxyl group, we achieved efficient regioselective synthesis using bulky ester in the intramolecular palladium coupling reaction.


Assuntos
Diabetes Mellitus Tipo 2/enzimologia , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Humanos , Simulação de Acoplamento Molecular
3.
Bioorg Med Chem Lett ; 14(15): 4019-22, 2004 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-15225718

RESUMO

A series of 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine derivatives was synthesized and evaluated as I kappaB kinase beta (IKK-beta) inhibitors. Modification of a novel IKK-beta inhibitor 1 (IKK-beta IC(50)=1500 nM, Cell IC(50)=8000 nM) at the 4-phenyl ring and 6-phenol group on the pyridine core ring resulted in a marked increased in biological activities. An optimized compound, 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile, exhibited excellent in vitro profiles (IKK-beta IC(50)=8.5 nM, Cell IC(50)=60 nM) and a strong oral efficacy in in vivo anti-inflammatory assays (significant effects at 1mg/kg, po in arachidonic acid-induced ear edema model in mice).


Assuntos
Anti-Inflamatórios/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Modelos Animais de Doenças , Edema/prevenção & controle , Humanos , Quinase I-kappa B , Cinética , Camundongos , Modelos Moleculares , Estrutura Molecular , Piridinas/síntese química , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-Atividade
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