ABSTRACTGlucocorticoids increase bone fragility in patients in a manner that is underestimated by bone mass measurement. This study aimed to determine if the adult mouse could model this bone strength/bone mass discrepancy. Forty‐two 13‐week‐old BALB/cJ mice were randomized into vehicle and glucocorticoid groups, implanted with vehicle or 6‐methylprednisolone pellets, and necropsied after 60 and 120 days. Bone strength and bone mass/microarchitecture were assessed at the right central femur (CF; cortical‐bone–rich) and sixth lumbar vertebral body (LVB6; trabecular‐bone–rich). Bound water (BW) of the whole right femur was analyzed by proton‐nuclear magnetic resonance (1H‐NMR) relaxometry. Data were analyzed by two‐factor ANOVA with time (day 60 and day 120) and treatment (vehicle and glucocorticoid) as main effects for all data. Significant interactions were further analyzed with a Tukey's post hoc test. Most bone strength measures in the CF were lower in the glucocorticoid group, regardless of the duration of treatment, with no time × treatment interaction. However, bone mass measures in the CF showed a significant time × treatment interaction (p = 0.0001). Bone strength measures in LVB6 showed a time × treatment interaction (p < 0.02) such that LVB6 strength was lower after 120 days of glucocorticoids compared with 120 days of vehicle treatment. Whole‐femur–BW was lower with both glucocorticoid treatment (p = 0.0001) and time (p < 0.02), with a significant time × treatment interaction (p = 0.005). Glucocorticoid treatment of male BALB/cJ mice resulted in the lowering of bone strength in both cortical and trabecular bone that either appeared earlier or was greater than the treatment‐related changes in bone mass/microarchitecture. The adult mouse may be a good model for investigating the bone strength/mass discrepancy observed in glucocorticoid‐treated patients. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

01 Jan 2019·Bioorganic & Medicinal ChemistryQ3 · MEDICINE

Synthesis and biological evaluation of BMS-986120 and its deuterated derivatives as PAR4 antagonists

Q3 · MEDICINE

Article

Author: Chen, Panpan ; Sun, Hongbin ; Chen, Fangjun ; Kong, Yi ; Song, Hangyu ; Xu, Qinglong ; Chen, Cai ; Ren, Shenhong

BMS-986120 is a PAR4 antagonist that is being investigated as an antiplatelet agent in phase I clinical trial. An improved synthesis of BMS-986120 has been developed. Based on the novel synthetic approach to BMS-986120, a series of deuterated derivatives of BMS-986120 have been synthesized and biologically evaluated to search for more potent antiplatelet agents. The in vitro antiplatelet assay by turbidimetry demonstrated that PC-2 and PC-6 had IC₅₀ values of 6.30 nM and 6.97 nM, respectively, versus BMS-986120 with an IC₅₀ of 7.80 nM. The result of in vitro metabolic stability study showed that all of the deuterated compounds had similar half-life (T_1/2) and intrinsic clearance (Clint) in comparison with BMS-986120. Further probing the metabolic profile of BMS-986120 is worth being conducted.

01 Jan 2019·Analytical and Bioanalytical ChemistryQ2 · CHEMISTRY

Analysis of corticosteroids in samples of animal origin using QuEChERS and ultrahigh-performance liquid chromatography coupled to high-resolution mass spectrometry

Q2 · CHEMISTRY

Article

Author: Beguiristain, Iñaki ; Rúbies, Antoni ; Granados, Mercè ; Alongi, Angelina

A rapid and sensitive method for the confirmatory analysis of eight synthetic corticosteroids (betamethasone, dexamethasone, prednisolone, 6-methylprednisolone, triamcinolone, flumethasone, beclomethasone, fluocinolone acetonide) is proposed. The method is useful for detecting illegal treatments in different animal species. It consists of an extraction and cleanup using the quick, easy, cheap, effective, rugged, and safe (QuEChERS) strategy. Quantitative determination is achieved by ultrahigh-performance liquid chromatography coupled to high-resolution mass spectrometry with heated electrospray ionization in negative mode. Quantification is performed using surrogate matrix-matched standard calibration curve with dexamethasone-D₄ as the internal standard. The method was validated for analyzing liver samples according to the criteria established by Decision 2002/657/EC. Linearity was assessed in the 1-10 μg kg^-1 range and linear correlation coefficients were over 0.99 for all the analytes. CCα ranged from 0.04 to 0.16 μg kg^-1 for substances without maximum residue limit. The method allows confident quantification and confirmation of corticosteroids in liver samples, and its simplicity makes it suitable for analyzing large numbers of samples.

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