RESUMEN
A series of non-steroidal GPBAR1 (TGR5) agonists was developed from a hit in a high-throughput screening campaign. Lead identification efforts produced biphenyl-4-carboxylic acid derivative (R)-22, which displayed a robust secretion of PYY after oral administration in a degree that can be correlated with the unbound plasma concentration. Further optimisation work focusing on reduction of the lipophilicity provided the 1-phenylpiperidine-4-carboxylic acid derivative (R)-29 (RO5527239), which showed an improved secretion of PYY and GLP-1, translating into a significant reduction of postprandial blood glucose excursion in an oral glucose tolerance test in DIO mice.
Asunto(s)
Glucemia/efectos de los fármacos , Descubrimiento de Drogas , Oximas/síntesis química , Propano/análogos & derivados , Receptores Acoplados a Proteínas G/agonistas , Administración Oral , Animales , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Oximas/química , Oximas/farmacología , Propano/sangre , Propano/síntesis química , Propano/química , Propano/farmacologíaRESUMEN
Design, synthesis, and SAR are described for a class of DPP-IV inhibitors based on aminobenzo[a]quinolizines with non-aromatic substituents in the S1 specificity pocket. One representative thereof, carmegliptin (8p), was chosen for clinical development. Its X-ray structure in complex with the enzyme and early efficacy data in animal models of type 2 diabetes are also presented.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Diseño de Fármacos , Hipoglucemiantes/síntesis química , Quinolizinas/síntesis química , Animales , Ensayos Clínicos Fase II como Asunto , Cristalografía por Rayos X , Preparaciones de Acción Retardada , Diabetes Mellitus Tipo 2/enzimología , Diabetes Mellitus Tipo 2/metabolismo , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Perros , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/uso terapéutico , Macaca fascicularis , Ratones , Quinolizinas/administración & dosificación , Quinolizinas/uso terapéutico , Ratas , Ratas Wistar , Ratas ZuckerRESUMEN
Synthesis and SAR are described for a structurally distinct class of DPP-IV inhibitors based on aminobenzo[a]quinolizines bearing (hetero-)aromatic substituents in the S1 specificity pocket. The m-(fluoromethyl)-phenyl derivative (S,S,S)-2g possesses the best fit in the S1 pocket. However, (S,S,S)-2i, bearing a more hydrophilic 5-methyl-pyridin-2-yl residue as substituent for the S1 pocket, displays excellent in vivo activity and superior drug-like properties.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores de la Dipeptidil-Peptidasa IV/química , Quinolizinas/química , Animales , Cristalografía por Rayos X , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Humanos , Inhibidores de Proteasas/química , Inhibidores de Proteasas/metabolismo , Inhibidores de Proteasas/farmacología , Quinolizinas/metabolismo , Quinolizinas/farmacología , Ratas , Ratas ZuckerRESUMEN
BACKGROUND: Somatostatin regulates numerous endocrine processes, including glucose homeostasis. The contribution and effects of the 5 somatostatin receptors are still unclear, in part due to the lack of suitable subtype specific receptor antagonists. We explored the effects of two novel, non-peptidic, orally bioavailable somatostatin receptor subtype 5 antagonists named Compound A and Compound B on glycemia in animal models of type 2 diabetes after an initial in vitro characterization. METHODS AND RESULTS: Compound A led to a dose-dependent decrease in glucose and insulin excursions during an OGTT in Zucker (fa/fa) rats after single treatment by up to 17% and 49%, respectively. Diet-induced obese mice showed after three weeks treatment with compounds A and B a dose-dependent decrease of the glucose excursion of up to 45% and 37%, respectively. In contrast to the acute effect observed in Zucker rats, Compound A showed a dose-dependent insulin increase by up to 72%, whereas body weight, liver triglycerides, ALT and AST were dose-dependently decreased. CONCLUSIONS: SSTR5 antagonists have the potential for short- and long-term improvements of the glucose homeostasis in rodent models of type 2 diabetes. Further work on the mechanism and the relevance for human disease is warranted.