RESUMO
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
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
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
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
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-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
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.
Assuntos
Inibidores da Dipeptidil Peptidase IV , Oxidiazóis/administração & dosagem , Oxidiazóis/farmacologia , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/farmacologia , Administração Oral , Animais , Sítios de Ligação , Disponibilidade Biológica , Cães , Ativação Enzimática/efeitos dos fármacos , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Humanos , Modelos Moleculares , Conformação Molecular , Oxidiazóis/química , Inibidores de Proteases/química , Conformação Proteica , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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
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
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
anti-Substituted biaryl beta-methylphenylalanine derived amides have been shown to be potent DPP-IV inhibitors that suffer from suboptimal selectivity and pharmacokinetics. This letter describes the substitution of the beta-methyl substituent with beta-polar substituents, culminating in the discovery of a beta-dimethylamide substituted phenylalanine derivative with an excellent potency, selectivity, and pharmacokinetic profile.
Assuntos
Dipeptidil Peptidase 4/química , Fenilalanina/síntese química , Fenilalanina/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Administração Oral , Animais , Glicemia/metabolismo , Proteínas de Ligação a DNA/metabolismo , Dipeptidil Peptidase 4/metabolismo , Teste de Tolerância a Glucose , Humanos , Camundongos , Estrutura Molecular , Fenilalanina/farmacocinética , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-Atividade , Especificidade por Substrato , Transativadores/metabolismo , Regulador Transcricional ERGRESUMO
anti-Substituted beta-methylphenylalanine derived amides have been shown to be potent DPP-IV inhibitors exhibiting excellent selectivity over both DPP8 and DPP9. These are among the most potent compounds reported to date lacking an electrophilic trap. The most potent compound among these is 5-oxo-1,2,4-oxadiazole 44, which is a 3 nM DPP-IV inhibitor.
Assuntos
Dipeptidil Peptidase 4/efeitos dos fármacos , Fenilalanina/farmacologia , Inibidores de Proteases/farmacologia , Fenilalanina/química , Inibidores de Proteases/químicaRESUMO
A series of beta-aminoacylpiperidines bearing various fused five-membered heterocyclic rings was synthesized as dipeptidyl peptidase IV inhibitors. Potent and relatively selective inhibition could be obtained, depending on choice of heterocycle, regioisomerism, and substitution. In particular, one analog (74, DPP-IV IC50=26 nM) exhibited good oral bioavailability and acceptable half-life in the rat, albeit with rather high clearance.
Assuntos
Dipeptidil Peptidase 4/metabolismo , Piperidinas/síntese química , Piperidinas/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Isoxazóis , Oxazóis , Piperidinas/química , Inibidores de Proteases/química , Pirazóis , TiazóisRESUMO
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
In-house screening of the Merck sample collection identified proline derived homophenylalanine 3 as a DPP-IV inhibitor with modest potency (DPP-IV IC50=1.9 microM). Optimization of 3 led to compound 37, which is among the most potent and selective DPP-IV inhibitors discovered to date.
Assuntos
Dipeptidil Peptidase 4/metabolismo , Prolina/análogos & derivados , Prolina/síntese química , Inibidores de Proteases/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Técnicas In Vitro , Prolina/química , Prolina/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Modification of in-house screening lead beta-aminoacyl proline 8 gave an equipotent thiazolidide 9. Extensive SAR studies on the phenyl ring of 9 led to the discovery of a novel series of potent and selective DP-IV inhibitors. Introduction of a fluorine at the 2-position proved to be crucial for the potency of this series. The 2,5-difluoro (22q) and 2,4,5-trifluoro (22t) analogues were potent inhibitors of DP-IV (IC(50)=270, 119nM, respectively).
Assuntos
Aminobutiratos/síntese química , Dipeptidil Peptidase 4/metabolismo , Inibidores de Proteases/síntese química , Aminobutiratos/química , Aminobutiratos/farmacologia , Animais , Disponibilidade Biológica , Meia-Vida , Metilação , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologiaRESUMO
Incorporation of a fluorophenyl beta-amino amide moiety into piperazine screening lead 2 has resulted in the discovery of a structurally novel series of potent and selective DP-IV inhibitors. Simplification of the molecule and incorporation of multiple fluorine atoms on the phenyl ring has provided low molecular weight analogs such as compound 32, which is a 19nM DP-IV inhibitor with >4000-fold selectivity over QPP.
Assuntos
Dipeptidil Peptidase 4/metabolismo , Piperazinas/farmacologia , Inibidores de Proteases/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Meia-Vida , Técnicas In Vitro , Masculino , Microssomos Hepáticos/metabolismo , Piperazinas/síntese química , Piperazinas/química , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A diastereoselective synthesis was used to prepare a series of (3-substituted-cyclopentyl and -cyclohexyl)glycine pyrrolidides and thiazolidides. The three chiral centers were generated in an unambiguous, stereochemically defined manner. Inhibitory activity was dependent on the configuration at each stereocenter and on the nature of the 3-substituent. In the cyclopentylglycine pyrrolidide series, high potency against dipeptidyl peptidase IV and good selectivity could be achieved.