RESUMEN
High-affinity, functionally potent, urea-based antagonists of CCR1 have been discovered. Modulation of PXR transactivation has revealed the selective and orally bioavailable CCR1 antagonist BMS-817399 (29), which entered clinical trials for the treatment of rheumatoid arthritis.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Descubrimiento de Drogas , Piperidinas/farmacología , Receptores CCR1/antagonistas & inhibidores , Urea/análogos & derivados , Valina/análogos & derivados , Animales , Disponibilidad Biológica , Ensayos Clínicos Fase II como Asunto , Células Hep G2 , Humanos , Masculino , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Piperidinas/metabolismo , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Receptor X de Pregnano , Conformación Proteica , Receptores CCR1/química , Receptores CCR1/metabolismo , Receptores de Esteroides/metabolismo , Especificidad de la Especie , Urea/metabolismo , Urea/farmacocinética , Urea/farmacología , Urea/uso terapéutico , Valina/metabolismo , Valina/farmacocinética , Valina/farmacología , Valina/uso terapéuticoRESUMEN
The thermal properties of three matrix metalloproteinase (MMP) inhibitors were investigated using a variety of instrumental methods. Differential scanning calorimetry revealed highly exothermic processes for all compounds above 200°C, and thermogravimetric analysis resulted in significant step-wise weight losses at the temperatures corresponding to the exothermic transitions. Hot stage microscopy observations for several compounds showed evolution of gas bubbles from crystals at temperatures that correlated with the exotherms. Thermal decomposition involving the hydroxamic acid functional group was suspected and further evaluated using various analytical techniques including reversed-phase HPLC, LC-MS-MS, TGA-FTIR and NMR. The mechanism proposed in the thermal decomposition involves a Lossen Rearrangement to form a dimeric species containing a urea linkage.
Asunto(s)
Dimerización , Calor , Inhibidores de la Metaloproteinasa de la Matriz , Rastreo Diferencial de Calorimetría , Cromatografía Líquida de Alta Presión , Cromatografía Liquida , Espectroscopía de Resonancia Magnética , Metaloproteinasas de la Matriz/química , Modelos Químicos , Espectroscopía Infrarroja por Transformada de Fourier , Espectrometría de Masas en Tándem , Tecnología Farmacéutica , Temperatura , TermogravimetríaRESUMEN
Roxifiban was found to exist in two polymorphic forms. The polymorphs were detected by X-ray powder diffraction and solid-state carbon nuclear magnetic resonance. A slight difference between the two polymorphs was also detected by isothermal microcalorimetry. However, no differences were observed by differential scanning calorimetry, infrared, or Raman spectroscopy. Solubility studies as a function of temperature in a discriminating solvent system permitted characterization of the thermodynamics of the polymorphs. The enthalpy of solution at 25 degrees C was 8.1 kcal/mol and 8.9 kcal/mol for Form I and Form II, respectively, and the thermodynamic transition point was 132 degrees C. The data confirm that the polymorphs are enantiotropic. Form II is the thermodynamically stable crystal form over the practical range of drug substance storage and handling and dosage form processing and storage. However, Form I has been kinetically stable after storage for more than 36 months at 25 degrees C/60% relative humidity with no conversion to Form II occurring.
Asunto(s)
Amidinas/análisis , Amidinas/química , Isoxazoles/análisis , Isoxazoles/química , Calorimetría/métodos , Química FarmacéuticaRESUMEN
Roxifiban, an experimental antithrombotic prodrug, exists as crystalline forms I and II. A quantitative solid-state nuclear magnetic resonance (NMR) method was developed to characterize the two polymorphs of roxifiban. The differences in the NMR spectra of the polymorphs were utilized in analyses of physical blends of the pure crystalline forms to establish a calibration curve. A detection limit of 9% form II in form I was determined from analysis of a 10% form II blend. Solid-state NMR was a valuable technique to quantify the polymorphic purity of roxifiban where other techniques such as differential scanning calorimetry (DSC) could not be used for this purpose.
