RESUMEN
Liquid chromatography-mass spectrometry (LC-MS) has been widely used throughout biotherapeutic development. However, its implementation in GMP-compliant commercial quality control (QC) laboratories remains a challenge. In this publication, we describe the covalidation and implementation of an automated, high-throughput, and GMP compliant subunit LC-MS method for monitoring antibody oxidation for commercial product release and stability testing. To our knowledge, this is the first report describing the implementation of a high-resolution LC-MS method in commercial QC laboratories for product release and stability testing in the biopharmaceutical industry. This work paves the road for implementing additional LC-MS methods to modernize testing in commercial QC with more targeted control of product quality.
Asunto(s)
Anticuerpos/análisis , Cromatografía Liquida , Laboratorios , Espectrometría de Masas , Control de CalidadRESUMEN
3-(S)-Pyrimidin-5-yl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5e) and 3-(S)-(methylpyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5f) were identified as potent and selective antagonists of the alpha(v)beta(3) receptor. These compounds have excellent in vitro profiles (IC(50) = 0.07 and 0.08 nM, respectively), significant unbound fractions in human plasma (6 and 4%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in an in vivo model of bone turnover following once-daily oral administration, these two compounds were selected for clinical development for the treatment of osteoporosis.
Asunto(s)
Integrinas/antagonistas & inhibidores , Naftiridinas/farmacología , Osteoporosis/tratamiento farmacológico , Receptores de Vitronectina/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Densidad Ósea/efectos de los fármacos , Resorción Ósea/tratamiento farmacológico , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Femenino , Humanos , Concentración 50 Inhibidora , Integrinas/metabolismo , Macaca mulatta , Modelos Moleculares , Naftiridinas/química , Naftiridinas/farmacocinética , Osteoporosis/prevención & control , Ovariectomía , Ratas , Ratas Sprague-Dawley , Receptores de Vitronectina/metabolismo , Relación Estructura-ActividadRESUMEN
Potent non-peptidic alpha(v)beta(3) antagonists have been prepared incorporating various beta-amino acids as aspartic acid mimetics. Modification of the beta-alanine 3-substituents alters the potency and physicochemical properties of these receptor antagonists and in some cases provides orally bioavailable alpha(v)beta(3) inhibitors.