RESUMEN
Inhibition of DPP-IV enzyme has taken centre stage as a validated drug target for type 2 diabetes therapy and as a result of research efforts done towards developing effective DPP-IV inhibitors, the first clinical candidate of this class came in focus in 1998. Thus, from 1998 to 2013, these 16-years have witnessed heightened research activities in the discovery and development of clinically relevant inhibitors of DPP-IV as antidiabetic agents. The effective DPP-IV inhibitors have played a key role in this endeavour and as result there are eight approved gliptins in the clinical usage while others are in different stages of clinical trials. A wide variety of DPP-IV inhibitors were synthesized and evaluated; and were classified into several categories based on their core structural features. In this article, classification of all the clinically relevant DPP-IV inhibitors based on selectivity, clinical efficacy and safety profiles is reviewed in terms of generations. This review also encompasses clinical phase wise discussion, developmental progress, chemistry and binding modes of all clinical DPP-IV inhibitors. In addition, major challenges facing the future design and development of safe clinical DPP-IV inhibitor are also briefly mentioned.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Hipoglucemiantes/uso terapéutico , Animales , Ensayos Clínicos como Asunto , Dipeptidil Peptidasa 4/química , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/metabolismo , Peptidomiméticos/química , Peptidomiméticos/metabolismo , Unión ProteicaRESUMEN
The present study describes the synthesis of a series of new 4-aminoquinoline-derived thiazolidines and evaluation of their antimalarial activity against a NF-54 strain of Plasmodium falciparum in vitro and N-67 strain of Plasmodium yoelii in vivo. Among the series, two compounds, 2-(4-chloro-phenyl)-thiazolidine-4-carboxylic acid [2-(7-chloro-quinolin-4-ylamino)-ethyl]-amide hydrochloride (14) and 2-(2,6-dichloro-phenyl)-thiazolidine-4-carboxylic acid [2-(7-chloro-quinolin-4-ylamino)-ethyl]-amide hydrochloride (22) exhibited significant suppression of parasitaemia in the in vivo assay. All the analogues were found to form strong complex with haematin and inhibited the ß-haematin formation in vitro. These results suggest that these compounds act on heme polymerization target.
Asunto(s)
Aminoquinolinas/química , Antimaláricos/síntesis química , Antimaláricos/farmacología , Hemo/química , Animales , Antimaláricos/química , Técnicas de Química Sintética , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Hemoproteínas/metabolismo , Malaria/tratamiento farmacológico , Ratones , Plasmodium falciparum/efectos de los fármacos , Polimerizacion , Tiazolidinas/químicaRESUMEN
In general nucleoside analogues were found to possess in vitro amoebicidal property against trophozoites of Entamoeba histolytica. The acid-labile nature of these compounds completely destroyed their ability to cure caecal amoebiasis of rats. However the therapeutic efficacy of one of these compounds yielded most promising results, with 10% cures when it was administered as enteric coated formulation.