RESUMEN
In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Compuestos Heterocíclicos con 2 Anillos/farmacología , Hipoglucemiantes/farmacología , Piranos/farmacología , Animales , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Inhibidores de la Dipeptidil-Peptidasa IV/toxicidad , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Compuestos Heterocíclicos con 2 Anillos/toxicidad , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/toxicidad , Piranos/síntesis química , Piranos/farmacocinética , Piranos/toxicidad , Relación Estructura-ActividadRESUMEN
There has been a growing interest in amorphous solid dispersions for bioavailability enhancement in drug discovery. Spray drying, as shown in this study, is well suited to produce prototype amorphous dispersions in the Candidate Selection stage where drug supply is limited. This investigation mapped the processing window of a micro-spray dryer to achieve desired particle characteristics and optimize throughput/yield. Effects of processing variables on the properties of hypromellose acetate succinate were evaluated by a fractional factorial design of experiments. Parameters studied include solid loading, atomization, nozzle size, and spray rate. Response variables include particle size, morphology and yield. Unlike most other commercial small-scale spray dryers, the ProCepT was capable of producing particles with a relatively wide mean particle size, ca. 2-35 µm, allowing material properties to be tailored to support various applications. In addition, an optimized throughput of 35 g/hour with a yield of 75-95% was achieved, which affords to support studies from Lead-identification/Lead-optimization to early safety studies. A regression model was constructed to quantify the relationship between processing parameters and the response variables. The response surface curves provide a useful tool to design processing conditions, leading to a reduction in development time and drug usage to support drug discovery.