ABSTRACT
ASP3026 (N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N'-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine) was developed in Astellas Pharma Inc. as a novel and selective inhibitor of the fusion protein EML4-ALK. We investigated the thermodynamic stability of five polymorphs of ASP3026 (A01, A02, A03, A04, and A05) in detail. To determine the most stable form at ambient temperature, powder X-ray diffraction, differential scanning calorimetry, and solubility measurements were conducted. Of the five polymorphs, A04 was the most stable and A05 was the least stable. The relationship between A04 and A03 and A04 and A01 were mutually monotropic, while that between A01 and A02 was enantiotropic. The transition temperature from A02 to A01 was estimated as 325 K. A02 was more thermodynamically stable at ambient temperature than A01. Furthermore, the method to estimate polymorphic transition temperatures using solution calorimetry was found to be effective. The systematic characterization of ASP3026 polymorphs presented in this study enables the selective crystallization of the most stable form and design of solid formulations.
Subject(s)
Protein Kinase Inhibitors/chemistry , Sulfones/chemistry , Thermodynamics , Triazines/chemistry , Calorimetry, Differential Scanning , Crystallization , Humans , Oncogene Proteins, Fusion/antagonists & inhibitors , Powder Diffraction , Solubility , Transition Temperature , X-Ray DiffractionABSTRACT
Hyperuricemia has recently been recognized to not only be a predictor of cardiovascular disease but also a marker of metabolic syndrome. We examined the association between uric acid levels and various clinical parameters, including the components of metabolic syndrome, in essential hypertension. One hundred forty-six untreated Japanese hypertensive patients (mean 58.3 years) without overt cardiovascular disease were divided into low and high uric acid groups by the median uric acid value (cut-off: 6.3 for men and 4.4 mg/dL for women). The high uric acid group had higher serum creatinine (0.74 vs. 0.67 mg/dL, p = 0.019) and a larger body mass index (BMI) (25.2 vs. 23.6 kg/m(2), p = 0.018) compared to the low group. Men from the high uric acid group were younger and had higher blood pressure (BP) than men from the low group. Uric acid levels were correlated with creatinine in both genders, with blood pressure, triglycerides in men only, and with BMI, fasting glucose in women only. Multiple regression analysis also indicated a significant correlation of uric acid with creatinine in both genders, with triglycerides in men, and with glucose in women. Metabolic syndrome (modified NCEP-ATPIII definition) was found in 37.0% of the high uric acid group (men 45.0, women 27.3%) and 20.8% of the low group. Results suggest that an increase of uric acid is associated with impaired renal function and constitutes a risk factor for metabolic syndrome. Uric acid may also be a useful index for initial risk stratification of untreated patients with essential hypertension.
