RESUMEN
We report a design strategy to obtain potent DPP-4 inhibitors by incorporating salt bridge formation with Lys554 in the S1' pocket. By applying the strategy to the previously identified templates, quinoline 4 and pyridines 16a, 16b, and 17 have been identified as subnanomolar or nanomolar inhibitors of human DPP-4. Docking studies suggested that a hydrophobic interaction with Tyr547 as well as the salt bridge interaction is important for the extremely high potency. The design strategy would be useful to explore a novel design for DPP-4 inhibitors having a distinct structure with a unique binding mode.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Piridinas/química , Piridinas/farmacología , Quinolinas/química , Quinolinas/farmacología , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4/química , Dipeptidil Peptidasa 4/metabolismo , Diseño de Fármacos , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Simulación del Acoplamiento Molecular , Ratas Sprague-Dawley , Ratas Wistar , Relación Estructura-ActividadRESUMEN
The design, synthesis, and structure-activity relationships of a new class of potent and orally active non-peptide dipeptidyl peptidase IV (DPP-4) inhibitors, 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolones, are described. We hypothesized that the 4-phenyl group of the isoquinolone occupies the S1 pocket of the enzyme, the 3-aminomethyl group forms an electrostatic interaction with the S2 pocket, and the introduction of a hydrogen bond donor onto the 6- or 7-substituent provides interaction with the hydrophilic region of the enzyme. Based on this hypothesis, intensive research focused on developing new non-peptide DPP-4 inhibitors has been carried out. Among the compounds designed in this study, we identified 2-[(3-aminomethyl-2-(2-methylpropyl)-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)oxy]acetamide (35a) as a potent, selective, and orally bioavailable DPP-4 inhibitor, which exhibited in vivo efficacy in diabetic model rats. Finally, X-ray crystallography of 35a in a complex with the enzyme validated our hypothesized binding mode and identified Lys554 as a new target-binding site available for DPP-4 inhibitors.
Asunto(s)
Dipeptidil Peptidasa 4/efectos de los fármacos , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Hipoglucemiantes/síntesis química , Isoquinolinas/síntesis química , Administración Oral , Animales , Glucemia , Células CACO-2 , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4/análisis , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/análisis , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/antagonistas & inhibidores , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/efectos de los fármacos , Diseño de Fármacos , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Isoquinolinas/administración & dosificación , Isoquinolinas/farmacología , Isoquinolinas/uso terapéutico , Terapia Molecular Dirigida , Péptidos/metabolismo , Quinolonas/administración & dosificación , Quinolonas/síntesis química , Quinolonas/química , Quinolonas/farmacología , Quinolonas/uso terapéutico , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Dipeptidyl peptidase IV (DPP-4) inhibition is a validated therapeutic option for type 2 diabetes, exhibiting multiple antidiabetic effects with little or no risk of hypoglycemia. In our studies involving non-covalent DPP-4 inhibitors, a novel series of quinoline-based inhibitors were designed based on the co-crystal structure of isoquinolone 2 in complex with DPP-4 to target the side chain of Lys554. Synthesis and evaluation of designed compounds revealed 1-[3-(aminomethyl)-4-(4-methylphenyl)-2-(2-methylpropyl)quinolin-6-yl]piperazine-2,5-dione (1) as a potent, selective, and orally active DPP-4 inhibitor (IC50=1.3 nM) with long-lasting ex vivo activity in dogs and excellent antihyperglycemic effects in rats. A docking study of compound 1 revealed a hydrogen-bonding interaction with the side chain of Lys554, suggesting this residue as a potential target site useful for enhancing DPP-4 inhibition.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Quinolinas/química , Quinolinas/uso terapéutico , Animales , Células CACO-2 , Línea Celular , Dipeptidil Peptidasa 4/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Perros , Femenino , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Lisina/metabolismo , Quinolinas/farmacocinética , Quinolinas/farmacología , Ratas , Ratas WistarRESUMEN
Inhibition of dipeptidyl peptidase IV (DPP-4) is an exciting new approach for the treatment of diabetes. To date there has been no DPP-4 chemotype possessing a carboxy group that has progressed into clinical trials. Originating from the discovery of the structurally novel quinoline derivative 1, we designed novel pyridine derivatives containing a carboxy group. In our design, the carboxy group interacted with the targeted amino acid residues around the catalytic region and thereby increased the inhibitory activity. After further optimization, we identified a hydrate of [5-(aminomethyl)-6-(2,2-dimethylpropyl)-2-ethyl-4-(4-methylphenyl)pyridin-3-yl]acetic acid (30c) as a potent and selective DPP-4 inhibitor. The desired interactions with the critical active-site residues, such as a salt-bridge interaction with Arg125, were confirmed by X-ray cocrystal structure analysis. In addition, compound 30c showed a desired preclinical safety profile, and it was encoded as TAK-100.
Asunto(s)
Acetatos/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Hipoglucemiantes/síntesis química , Piridinas/síntesis química , Acetatos/farmacocinética , Acetatos/farmacología , Animales , Dominio Catalítico , Cristalografía por Rayos X , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Perros , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Modelos Moleculares , Conformación Proteica , Piridinas/farmacocinética , Piridinas/farmacología , Quinolinas/síntesis química , Quinolinas/farmacocinética , Quinolinas/farmacología , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
We have previously discovered nicotinic acid derivative 1 as a structurally novel dipeptidyl peptidase IV (DPP-4) inhibitor. In this study, we obtained the X-ray co-crystal structure between nicotinic acid derivative 1 and DPP-4. From these X-ray co-crystallography results, to achieve more potent inhibitory activity, we targeted Arg125 as a potential amino acid residue because it was located near the pyridine core, and some known DPP-4 inhibitors were reported to interact with this residue. We hypothesized that the guanidino group of Arg125 could interact with two hydrogen-bond acceptors in a bidentate manner. Therefore, we designed a series of 3-pyridylacetamide derivatives possessing an additional hydrogen-bond acceptor that could have the desired bidentate interaction with Arg125. We discovered the dihydrochloride of 1-{[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-(2-methylpropyl)pyridin-3-yl]acetyl}-l-prolinamide (13j) to be a potent and selective DPP-4 inhibitor that could interact with the guanidino group of Arg125 in a unique bidentate manner.