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 ZuckerRESUMO
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 MolecularRESUMO
We report on the identification of 2-({6-[(3R)-3-amino-3-methylpiperidine-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidine-5-yl}methyl)-4-fluorobenzonitrile (DSR-12727) (7a) as a potent and orally active DPP-4 inhibitor without mechanism-based inactivation of CYP3A. Compound 7a showed good DPP-4 inhibitory activity (IC(50)=1.1 nM), excellent selectivity against related peptidases and other off-targets, good pharmacokinetic and pharmacodynamic profile, great in vivo efficacy in Zucker-fatty rat, and no safety concerns both in vitro and in vivo.
Assuntos
Inibidores do Citocromo P-450 CYP3A , Inibidores da Dipeptidil Peptidase IV/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Animais , Glicemia/metabolismo , Citocromo P-450 CYP3A/metabolismo , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/química , Cães , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Haplorrinos , Humanos , Masculino , Conformação Molecular , Pirazóis/síntese química , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Zucker , Estereoisomerismo , Relação Estrutura-Atividade , Fatores de TempoRESUMO
Structures containing the (R)-3-amino-3-methyl piperidine unit as a new pharmacophore moiety have been shown to possess moderate inhibitory activity for DPP-4 with good pharmacokinetics profile. One of these compounds was found to have good oral bioavailability and PK/PD profile in ZF-rat.
Assuntos
Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/química , Piperidinas/química , Pirimidinonas/química , Animais , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Humanos , Microssomos Hepáticos/metabolismo , Piperidinas/síntese química , Piperidinas/farmacocinética , Pirimidinonas/síntese química , Pirimidinonas/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Lurasidone is a novel antipsychotic agent with high affinity for dopamine D(2), 5-hydroxyltryptamine 5-HT(2A), and 5-HT(7) receptors. Lurasidone has negligible affinity for histamine H(1) and muscarinic M(1) receptors, which are thought to contribute to side effects such as weight gain, sedation, and worsening of cognitive deficits. Our interests focus on why lurasidone has such high selectivity for only a part of these aminergic G-protein coupled receptors (GPCRs) and the different binding profile from ziprasidone, which has the same benzisothiazolylpiperazine moiety as lurasidone. In order to address these issues, we constructed structural models of lurasidone-GPCR complexes by homology modeling of receptors, exhaustive docking of ligand, and molecular dynamics simulation-based refinement of complexes. This computational study gave reliable structural models for D(2), 5-HT(2A), and 5-HT(7), which had overall structural complementarities with a salt bridge anchor at the center of the lurasidone molecule, but not for H(1) and M(1) owing to steric hindrance between the norbornane-2,3-dicarboximide and/or cyclohexane part of lurasidone and both receptors. By comparison with the structural models of olanzapine-GPCRs and ziprasidone-GPCRs constructed using the same computational protocols, it was suggested that the bulkiness of the norbornane-2,3-dicarboximide part and the rigidity and the bulkiness of the cyclohexyl linker gave lurasidone high selectivity for the desired aminergic GPCRs. Finally, this structural insight was validated by a binding experiment of the novel benzisothiazolylpiperazine derivatives. This knowledge on the structural mechanism behind the receptor selectivity should help to design new antipsychotic agents with preferable binding profiles, and the established computational protocols realize virtual screening and structure-based drug design for other central nervous system drugs with desired selectivity for multiple targets.