RESUMO
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.
Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Descoberta de Drogas , Pirrolidinas/farmacologia , Animais , Cristalografia por Raios X , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/química , Cães , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Amidas/química , Inibidores da Dipeptidil Peptidase IV/química , Compostos Heterocíclicos com 2 Anéis/química , Piranos/química , Sulfonamidas/química , Animais , Sítios de Ligação , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Cães , Meia-Vida , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Piranos/síntese química , Piranos/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores da Dipeptidil Peptidase IV/síntese química , Compostos Heterocíclicos com 2 Anéis/síntese química , Piranos/síntese química , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Cães , Ativação Enzimática/efeitos dos fármacos , Teste de Tolerância a Glucose , Haplorrinos , Humanos , Concentração Inibidora 50 , Piranos/química , Piranos/farmacologia , Ratos , EstereoisomerismoRESUMO
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.
Assuntos
Cicloexanos/síntese química , Cicloexanos/farmacologia , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Animais , Disponibilidade Biológica , Cicloexanos/farmacocinética , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Meia-Vida , Piperidinas/farmacocinética , RatosRESUMO
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.
Assuntos
Química Farmacêutica/métodos , Inibidores da Dipeptidil Peptidase IV/síntese química , Imidazóis/síntese química , Piperidinas/química , Piperidinas/síntese química , Animais , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Cristalografia por Raios X/métodos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Cães , Desenho de Fármacos , Peptídeo 1 Semelhante ao Glucagon/química , Humanos , Hidrólise , Imidazóis/farmacologia , Concentração Inibidora 50 , Macaca mulatta , Camundongos , Piperidinas/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Ratos , Fosfato de Sitagliptina , Triazóis/síntese química , Triazóis/farmacologiaRESUMO
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.
Assuntos
Amidas/síntese química , Inibidores da Dipeptidil Peptidase IV , Piperazinas/síntese química , Pirazinas/síntese química , Triazóis/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Cristalografia por Raios X , Dipeptidil Peptidase 4/química , Cães , Teste de Tolerância a Glucose , Haplorrinos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Piperazinas/farmacocinética , Piperazinas/farmacologia , Pirazinas/farmacocinética , Pirazinas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/farmacocinética , Triazóis/farmacologiaRESUMO
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.
Assuntos
Alcenos/farmacocinética , Amidas/química , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Hidrocarbonetos Fluorados/farmacocinética , Hipoglicemiantes/farmacocinética , Microssomos Hepáticos/efeitos dos fármacos , Alcenos/síntese química , Animais , Inibidores da Dipeptidil Peptidase IV/síntese química , Hidrocarbonetos Fluorados/síntese química , Hipoglicemiantes/síntese química , Microssomos Hepáticos/patologia , Modelos Químicos , Mimetismo Molecular , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
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.
RESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidases/antagonistas & inibidores , Dipeptidil Peptidase 4 , Dipeptidil Peptidases e Tripeptidil Peptidases/antagonistas & inibidores , Hipoglicemiantes , Inibidores de Proteases/uso terapêutico , Animais , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/fisiologia , Cães , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/toxicidade , Isoleucina/análogos & derivados , Isoleucina/química , Isoleucina/uso terapêutico , Isoleucina/toxicidade , Isomerismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Inibidores de Proteases/toxicidade , Ratos , Proteínas Recombinantes/antagonistas & inibidores , Tiazóis/química , Tiazóis/uso terapêutico , Tiazóis/toxicidadeRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Hipoglicemiantes/síntese química , Fenilalanina/análogos & derivados , Inibidores de Proteases/síntese química , Triazóis/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Canais de Cálcio Tipo L/efeitos dos fármacos , Linhagem Celular , Cristalografia por Raios X , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Proteínas Musculares/antagonistas & inibidores , Músculo Esquelético/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5 , Fenilalanina/síntese química , Fenilalanina/química , Fenilalanina/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Coelhos , Canais de Sódio , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologiaRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Pirazinas/química , Pirazinas/farmacologia , Triazóis/química , Triazóis/farmacologia , Administração Oral , Animais , Sítios de Ligação , Bioquímica/métodos , Glicemia/análise , Cristalografia por Raios X , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Glucagon/sangue , Glucagon/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon , Teste de Tolerância a Glucose , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/efeitos dos fármacos , Conformação Proteica , Precursores de Proteínas/sangue , Precursores de Proteínas/efeitos dos fármacos , Pirazinas/farmacocinética , Ratos , Fosfato de Sitagliptina , Relação Estrutura-Atividade , Triazóis/farmacocinéticaRESUMO
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.
Assuntos
Inibidores da Dipeptidil Peptidase IV , Inibidores de Proteases/farmacologia , Pirimidinas/farmacologia , Desenho de Fármacos , Modelos Moleculares , Inibidores de Proteases/química , Pirimidinas/química , Relação Quantitativa Estrutura-AtividadeRESUMO
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.
Assuntos
Diabetes Mellitus/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV , Hipoglicemiantes/farmacologia , Piperidinas/farmacologia , Inibidores de Proteases/farmacologia , Amidas/química , Humanos , Hipoglicemiantes/uso terapêutico , Piperidinas/química , Piperidinas/uso terapêutico , Inibidores de Proteases/química , Inibidores de Proteases/uso terapêuticoRESUMO
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.
Assuntos
Alanina/análogos & derivados , Cicloexanos/farmacologia , Inibidores da Dipeptidil Peptidase IV , Inibidores Enzimáticos/farmacologia , Fenilalanina/análogos & derivados , Administração Oral , Alanina/química , Alanina/farmacologia , Animais , Sítios de Ligação , Disponibilidade Biológica , Cristalografia por Raios X , Cicloexanos/química , Dipeptidil Peptidase 4/química , Inibidores Enzimáticos/química , Teste de Tolerância a Glucose , Camundongos , Modelos Moleculares , Estrutura Molecular , Fenilalanina/química , Fenilalanina/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores da Dipeptidil Peptidase IV , Piperidinas/química , Piperidinas/farmacologia , Animais , Área Sob a Curva , Disponibilidade Biológica , Meia-Vida , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Estrutura Molecular , Piperidinas/sangue , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Amidas/química , Inibidores da Dipeptidil Peptidase IV , Piperazinas/química , Inibidores de Proteases/farmacologia , Pirazinas/farmacologia , Triazóis/química , Animais , Inibidores de Proteases/síntese química , Pirazinas/química , Ratos , Fosfato de Sitagliptina , Relação Estrutura-Atividade , Triazóis/farmacologiaRESUMO
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.
Assuntos
Alanina/análogos & derivados , Inibidores da Dipeptidil Peptidase IV , Inibidores de Proteases/farmacologia , Administração Oral , Alanina/química , Alanina/farmacologia , Animais , Área Sob a Curva , Camundongos , Modelos Moleculares , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinéticaRESUMO
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.
Assuntos
Amidas/química , Amidas/farmacologia , Inibidores da Dipeptidil Peptidase IV , Piperazinas/química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Amidas/síntese química , Amidas/farmacocinética , Animais , Cristalografia por Raios X , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Modelos Moleculares , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , RatosRESUMO
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.
Assuntos
Inibidores de Adenosina Desaminase , Glicoproteínas/antagonistas & inibidores , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/farmacologia , Piridonas/administração & dosagem , Piridonas/farmacologia , Adenosina Desaminase/metabolismo , Administração Oral , Amidas/química , Animais , Disponibilidade Biológica , Dipeptidil Peptidase 4/metabolismo , Cães , Glicoproteínas/metabolismo , Humanos , Concentração Inibidora 50 , Macaca mulatta , Estrutura Molecular , Nitrogênio/química , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Piridonas/química , Piridonas/farmacocinética , Ratos , Sensibilidade e Especificidade , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
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.