RESUMEN
Novel potent and selective 5,6,5- and 5,5,6-tricyclic pyrrolidine dipeptidyl peptidase IV (DPP-4) inhibitors were identified. Structure-activity relationship (SAR) efforts focused on improving the intrinsic DPP-4 inhibition potency, increasing protease selectivity, and demonstrating clean ion channel and cytochrome P450 profiles while trying to achieve a pharmacokinetic profile suitable for once weekly dosing in humans.
Asunto(s)
Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Descubrimiento de Drogas , Pirrolidinas/farmacología , Animales , Cristalografía por Rayos X , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/química , Perros , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Pirrolidinas/síntesis química , Pirrolidinas/química , Ratas , Relación Estructura-ActividadRESUMEN
A series of novel substituted-[(3R)-amino-2-(2,5-difluorophenyl)]tetrahydro-2H-pyran analogs have been prepared and evaluated as potent, selective and orally active DPP-4 inhibitors. These efforts lead to the discovery of a long acting DPP-4 inhibitor, omarigliptin (MK-3102), which recently completed phase III clinical development and has been approved in Japan.
Asunto(s)
Amidas/química , Inhibidores de la Dipeptidil-Peptidasa IV/química , Compuestos Heterocíclicos con 2 Anillos/química , Piranos/química , Sulfonamidas/química , Animales , Sitios de Unión , Dipeptidil Peptidasa 4/química , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Perros , Semivida , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Piranos/síntesis química , Piranos/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
A series of novel tri-2,3,5-substituted tetrahydropyran analogs were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the series provided inhibitors with good DPP-4 potency and selectivity over other peptidases (QPP, DPP8, and FAP). Compound 23, which is very potent, selective, efficacious in the diabetes PD model, and has an excellent pharmacokinetic profile, is selected as a clinical candidate.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Piranos/síntesis química , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Perros , Activación Enzimática/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Haplorrinos , Humanos , Concentración 50 Inhibidora , Piranos/química , Piranos/farmacología , Ratas , EstereoisomerismoRESUMEN
A series of 4-amino cyclohexanes and 4-substituted piperidines were prepared and evaluated for inhibition of DPP-4. Analog 20q displayed both good DPP-4 potency and selectivity against other proteases, while derivative 20k displayed long half life and modest oral bioavailability in rat. The most potent analog, 3-(5-aminocarbonylpyridyl piperidine 53j, displayed excellent DPP-4 activity with good selectivity versus other proline enzymes.
Asunto(s)
Ciclohexanos/síntesis química , Ciclohexanos/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Animales , Disponibilidad Biológica , Ciclohexanos/farmacocinética , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Semivida , Piperidinas/farmacocinética , RatasRESUMEN
A new series of DPP-4 inhibitors derived from piperidine-fused benzimidazoles and imidazopyridines is described. Optimization of this class of DPP-4 inhibitors led to the discovery of imidazopyridine 34. The potency, selectivity, cross-species DMPK profiles, and in vivo efficacy of 34 is reported.
Asunto(s)
Química Farmacéutica/métodos , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Imidazoles/síntesis química , Piperidinas/química , Piperidinas/síntesis química , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Cristalografía por Rayos X/métodos , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Perros , Diseño de Fármacos , Péptido 1 Similar al Glucagón/química , Humanos , Hidrólisis , Imidazoles/farmacología , Concentración 50 Inhibidora , Macaca mulatta , Ratones , Piperidinas/farmacología , Pirazinas/síntesis química , Pirazinas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Fosfato de Sitagliptina , Triazoles/síntesis química , Triazoles/farmacologíaRESUMEN
A series of beta-aminoamides bearing triazolopiperazines have been discovered as potent, selective, and orally active dipeptidyl peptidase IV (DPP-4) inhibitors by extensive structure-activity relationship (SAR) studies around the triazolopiperazine moiety. Among these, compound 34b with excellent in vitro potency (IC50 = 4.3 nM) against DPP-4, high selectivity over other enzymes, and good pharmacokinetic profiles exhibited pronounced in vivo efficacy in an oral glucose tolerance test (OGTT) in lean mice. On the basis of these properties, compound 34b has been profiled in detail. Further refinement of the triazolopiperazines resulted in the discovery of a series of extremely potent compounds with subnanomolar activity against DPP-4 (42b- 49b), that is, 4-fluorobenzyl-substituted compound 46b, which is notable for its superior potency (IC50 = 0.18 nM). X-ray crystal structure determination of compounds 34b and 46b in complex with DPP-4 enzyme revealed that (R)-stereochemistry at the 8-position of triazolopiperazines is strongly preferred over (S) with respect to DPP-4 inhibition.
Asunto(s)
Amidas/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV , Piperazinas/síntesis química , Pirazinas/síntesis química , Triazoles/síntesis química , Amidas/farmacocinética , Amidas/farmacología , Animales , Cristalografía por Rayos X , Dipeptidil Peptidasa 4/química , Perros , Prueba de Tolerancia a la Glucosa , Haplorrinos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Piperazinas/farmacocinética , Piperazinas/farmacología , Pirazinas/farmacocinética , Pirazinas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Triazoles/farmacocinética , Triazoles/farmacologíaRESUMEN
The synthesis, selectivity, rat pharmacokinetic profile, and drug metabolism profiles of a series of potent fluoroolefin-derived DPP-4 inhibitors (4) are reported. A radiolabeled fluoroolefin 33 was shown to possess a high propensity to form reactive metabolites, thus revealing a potential liability for this class of DPP-4 inhibitors.
Asunto(s)
Alquenos/farmacocinética , Amidas/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Hidrocarburos Fluorados/farmacocinética , Hipoglucemiantes/farmacocinética , Microsomas Hepáticos/efectos de los fármacos , Alquenos/síntesis química , Animales , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Hidrocarburos Fluorados/síntesis química , Hipoglucemiantes/síntesis química , Microsomas Hepáticos/patología , Modelos Químicos , Imitación Molecular , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
AIMS: Since 2006, DPP-4 inhibitors have become established therapy for the treatment of type 2 diabetes. Despite sharing a common mechanism of action, considerable chemical diversity exists amongst members of the DPP-4 inhibitor class, raising the question as to whether structural differences may result in differentiated enzyme inhibition and antihyperglycaemic activity. METHODS: We have compared the binding properties of the most commonly used inhibitors and have investigated the relationship between their inhibitory potency at the level of the enzyme and their acute glucose-lowering efficacy. RESULTS: Firstly, using a combination of published crystal structures and in-house data, we demonstrated that the binding site utilized by all of the DPP-4 inhibitors assessed was the same as that used by neuropeptide Y, supporting the hypothesis that DPP-4 inhibitors are able to competitively inhibit endogenous substrates for the enzyme. Secondly, we ascertained that the enzymatic cleft of DPP-4 is a relatively large cavity which displays conformational flexibility to accommodate structurally diverse inhibitor molecules. Finally, we found that for all inhibitors, irrespective of their chemical structure, the inhibition of plasma DPP-4 enzyme activity correlates directly with acute plasma glucose lowering in mice. CONCLUSION: The common binding site utilized by different DPP-4 inhibitors enables similar competitive inhibition of the cleavage of the endogenous DPP-4 substrates. Furthermore, despite chemical diversity and a range of binding potencies observed amongst the DPP-4 inhibitors, a direct relationship between enzyme inhibition in the plasma and glucose lowering is evident in mice for each member of the classes studied.
RESUMEN
Dipeptidyl peptidase (DPP)-IV inhibitors are a new approach to the treatment of type 2 diabetes. DPP-IV is a member of a family of serine peptidases that includes quiescent cell proline dipeptidase (QPP), DPP8, and DPP9; DPP-IV is a key regulator of incretin hormones, but the functions of other family members are unknown. To determine the importance of selective DPP-IV inhibition for the treatment of diabetes, we tested selective inhibitors of DPP-IV, DPP8/DPP9, or QPP in 2-week rat toxicity studies and in acute dog tolerability studies. In rats, the DPP8/9 inhibitor produced alopecia, thrombocytopenia, reticulocytopenia, enlarged spleen, multiorgan histopathological changes, and mortality. In dogs, the DPP8/9 inhibitor produced gastrointestinal toxicity. The QPP inhibitor produced reticulocytopenia in rats only, and no toxicities were noted in either species for the selective DPP-IV inhibitor. The DPP8/9 inhibitor was also shown to attenuate T-cell activation in human in vitro models; a selective DPP-IV inhibitor was inactive in these assays. Moreover, we found DPP-IV inhibitors that were previously reported to be active in models of immune function to be more potent inhibitors of DPP8/9. These results suggest that assessment of selectivity of potential clinical candidates may be important to an optimal safety profile for this new class of antihyperglycemic agents.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidasas/antagonistas & inhibidores , Dipeptidil Peptidasa 4 , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/antagonistas & inhibidores , Hipoglucemiantes , Inhibidores de Proteasas/uso terapéutico , Animales , Dipeptidil Peptidasa 4/genética , Dipeptidil Peptidasa 4/fisiología , Perros , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/toxicidad , Isoleucina/análogos & derivados , Isoleucina/química , Isoleucina/uso terapéutico , Isoleucina/toxicidad , Isomerismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Inhibidores de Proteasas/toxicidad , Ratas , Proteínas Recombinantes/antagonistas & inhibidores , Tiazoles/química , Tiazoles/uso terapéutico , Tiazoles/toxicidadRESUMEN
A series of beta-substituted biarylphenylalanine amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the metabolic profile of early analogues led to the discovery of (2S,3S)-3-amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]pyridin-6-ylphenyl)butanamide (6), a potent, orally active DPP-4 inhibitor (IC(50) = 6.3 nM) with excellent selectivity, oral bioavailability in preclinical species, and in vivo efficacy in animal models. Compound 6 was selected for further characterization as a potential new treatment for type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4/metabolismo , Hipoglucemiantes/síntesis química , Fenilalanina/análogos & derivados , Inhibidores de Proteasas/síntesis química , Triazoles/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Canales de Calcio Tipo L/efectos de los fármacos , Línea Celular , Cristalografía por Rayos X , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Proteínas Musculares/antagonistas & inhibidores , Músculo Esquelético/metabolismo , Canal de Sodio Activado por Voltaje NAV1.5 , Fenilalanina/síntesis química , Fenilalanina/química , Fenilalanina/farmacología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Conejos , Canales de Sodio , Estereoisomerismo , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacologíaRESUMEN
A novel series of beta-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (1) is a potent, orally active DPP-IV inhibitor (IC(50) = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of compound 1, was selected for development as a potential new treatment for type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Hipoglucemiantes/farmacología , Pirazinas/química , Pirazinas/farmacología , Triazoles/química , Triazoles/farmacología , Administración Oral , Animales , Sitios de Unión , Bioquímica/métodos , Glucemia/análisis , Cristalografía por Rayos X , Dipeptidil Peptidasa 4/química , Dipeptidil Peptidasa 4/metabolismo , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Glucagón/sangre , Glucagón/efectos de los fármacos , Péptido 1 Similar al Glucagón , Prueba de Tolerancia a la Glucosa , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/efectos de los fármacos , Conformación Proteica , Precursores de Proteínas/sangre , Precursores de Proteínas/efectos de los fármacos , Pirazinas/farmacocinética , Ratas , Fosfato de Sitagliptina , Relación Estructura-Actividad , Triazoles/farmacocinéticaRESUMEN
A series of substituted imidazopiperidine amides has been prepared and evaluated for inhibition of dipeptidyl peptidase IV (DPP-4). Substitution at the 1- and 3-positions produced increased selectivity for DPP-4 relative to DPP-8 and DPP-9. Compounds in this series had IC(50) values as low as 5.8 nM for inhibition of DPP-4.
Asunto(s)
Diabetes Mellitus/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV , Hipoglucemiantes/farmacología , Piperidinas/farmacología , Inhibidores de Proteasas/farmacología , Amidas/química , Humanos , Hipoglucemiantes/uso terapéutico , Piperidinas/química , Piperidinas/uso terapéutico , Inhibidores de Proteasas/química , Inhibidores de Proteasas/uso terapéuticoRESUMEN
Molecular modeling was used to improve potency of the cyclohexylamine series. In addition, a 3-D QSAR method was used to gain insight for reducing off-target DPP-8/9 activities. Compounds 3, 4, and 5 were synthesized and found to be potent DPP-4 inhibitors, in particular 4 and 5 are designed to be highly selective against off-target DASH enzymes while maintaining potency on DPP-4.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores de Proteasas/farmacología , Pirimidinas/farmacología , Diseño de Fármacos , Modelos Moleculares , Inhibidores de Proteasas/química , Pirimidinas/química , Relación Estructura-Actividad CuantitativaRESUMEN
Various beta-amino amides containing triazolopiperazine heterocycles have been prepared and evaluated as potent, selective, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. These compounds display excellent oral bioavailability and good overall pharmacokinetic profiles in preclinical species. Moreover, in vivo efficacy in an oral glucose tolerance test in lean mice is demonstrated.
Asunto(s)
Amidas/química , Amidas/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV , Piperazinas/química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Amidas/síntesis química , Amidas/farmacocinética , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Modelos Moleculares , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , RatasRESUMEN
Substituted 3-aminopiperidines 3 were evaluated as DPP-4 inhibitors. The inhibitors showed good DPP-4 potency with superb selectivity over other peptidases (QPP, DPP8, and DPP9). Selected DPP-4 inhibitors were further evaluated for their hERG potassium channel, calcium channel, Cyp2D6, and pharmacokinetic profiles.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV , Piperidinas/química , Piperidinas/farmacología , Animales , Área Bajo la Curva , Disponibilidad Biológica , Semivida , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Estructura Molecular , Piperidinas/sangre , Ratas , Relación Estructura-ActividadRESUMEN
A novel series of 4-arylcyclohexylalanine DPP-4 inhibitors was synthesized and tested for inhibitory activity as well as selectivity over the related proline-specific enzymes DPP-8 and DPP-9. Optimization of this series led to 28 (DPP-4 IC(50)=4.8 nM), which showed an excellent pharmacokinetic profile across several preclinical species. Evaluation of 28 in an oral glucose tolerance test demonstrated that this compound effectively reduced glucose excursion in lean mice.
Asunto(s)
Alanina/análogos & derivados , Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores de Proteasas/farmacología , Administración Oral , Alanina/química , Alanina/farmacología , Animales , Área Bajo la Curva , Ratones , Modelos Moleculares , Inhibidores de Proteasas/administración & dosificación , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinéticaRESUMEN
A novel series of 4-aminophenylalanine and 4-aminocyclohexylalanine derivatives were designed and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4). The phenylalanine series afforded compounds such as 10 that were potent and selective (DPP-4, IC(50)=28nM), but exhibited limited oral bioavailability. The corresponding cyclohexylalanine derivatives such as 25 afforded improved PK exposure and efficacy in a murine OGTT experiment. The X-ray crystal structure of 25 bound to the DPP-4 active site is presented.
Asunto(s)
Alanina/análogos & derivados , Ciclohexanos/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores Enzimáticos/farmacología , Fenilalanina/análogos & derivados , Administración Oral , Alanina/química , Alanina/farmacología , Animales , Sitios de Unión , Disponibilidad Biológica , Cristalografía por Rayos X , Ciclohexanos/química , Dipeptidil Peptidasa 4/química , Inhibidores Enzimáticos/química , Prueba de Tolerancia a la Glucosa , Ratones , Modelos Moleculares , Estructura Molecular , Fenilalanina/química , Fenilalanina/farmacología , Relación Estructura-ActividadRESUMEN
A series of beta-aminoamides bearing triazolopiperazines has been prepared and evaluated as potent, selective, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. Efforts at optimization of the beta-aminoamide series, which ultimately led to the discovery of JANUVIA (sitagliptin phosphate, compound 1), are described.
Asunto(s)
Amidas/química , Inhibidores de la Dipeptidil-Peptidasa IV , Piperazinas/química , Inhibidores de Proteasas/farmacología , Pirazinas/farmacología , Triazoles/química , Animales , Inhibidores de Proteasas/síntesis química , Pirazinas/química , Ratas , Fosfato de Sitagliptina , Relación Estructura-Actividad , Triazoles/farmacologíaRESUMEN
anti-Substituted beta-methylphenylalanine derived amides have been shown to be potent DPP-IV inhibitors exhibiting excellent selectivity over both DPP8 and DPP9. The optimized compound exhibited good pharmacokinetic profiles in three preclinical species.
Asunto(s)
Inhibidores de la Adenosina Desaminasa , Glicoproteínas/antagonistas & inhibidores , Inhibidores de Proteasas/administración & dosificación , Inhibidores de Proteasas/farmacología , Piridonas/administración & dosificación , Piridonas/farmacología , Adenosina Desaminasa/metabolismo , Administración Oral , Amidas/química , Animales , Disponibilidad Biológica , Dipeptidil Peptidasa 4/metabolismo , Perros , Glicoproteínas/metabolismo , Humanos , Concentración 50 Inhibidora , Macaca mulatta , Estructura Molecular , Nitrógeno/química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , Piridonas/química , Piridonas/farmacocinética , Ratas , Sensibilidad y Especificidad , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
A novel series of oxadiazole based amides have been shown to be potent DPP-4 inhibitors. The optimized compound 43 exhibited excellent selectivity over a variety of DPP-4 homologs.