Effect of Basic and Acidic Additives on the Separation of Some Basic Drug Enantiomers on Polysaccharide‐Based Chiral Columns With Acetonitrile as Mobile Phase

The separation of enantiomers of 16 basic drugs was studied using polysaccharide‐based chiral selectors and acetonitrile as mobile phase with emphasis on the role of basic and acidic additives on the separation and elution order of enantiomers. Out of the studied chiral selectors, amylose phenylcarbamate‐based ones more often showed a chiral recognition ability compared to cellulose phenylcarbamate derivatives. An interesting effect was observed with formic acid as additive on enantiomer resolution and enantiomer elution order for some basic drugs. Thus, for instance, the enantioseparation of several β‐blockers (atenolol, sotalol, toliprolol) improved not only by the addition of a more conventional basic additive to the mobile phase, but also by the addition of an acidic additive. Moreover, an opposite elution order of enantiomers was observed depending on the nature of the additive (basic or acidic) in the mobile phase. Chirality 27:228–234, 2015. © 2015 Wiley Periodicals, Inc.     

Evaluation of Tetrahydropalmatine Enantiomers on the Activity of Five Cytochrome P450 Isozymes in Rats Using a Liquid Chromatography / Mass Spectrometric Method and a Cocktail Approach

The aim was to evaluate the effects of tetrahydropalmatine (THP) enantiomers on the activity of five cytochrome P450 (CYP450) isozymes in vivo. A liquid chromatography / mass spectrometric (LC‐MS) method was developed for simultaneous determination of five specific probe substrates including metoprolol (2D6), caffeine (1A2), dapsone (3A4), chlorzoxazone (2E1), and tolbutamide (2C9) in rat plasma. Analytes were separated with the mobile phase consisting of 0.1% acetic acid aqueous solution and acetonitrile in a gradient elution. The mass spectrometric detection via selected ion monitoring (SIM) was operated in both positive ion mode (for metoprolol m/z 268, caffeine m/z 195, and dapsone m/z 249) and negative ion mode (for chlorzoxazone m/z 168 and tolbutamide m/z 269) in the same run. Linear correlation was obtained (r² > 0.99) over the concentration range of 0.050–25.0 µg/mL for caffeine and dapsone, 0.025–10.0 µg/mL for metoprolol, 0.050–50.0 µg/mL for chlorzoxazone, and 0.25–100.0 µg/mL for tolbutamide. Intra‐ and interday precision were less than 12.09%. The matrix effect ranged from 87.50% to 109.25% and the absolute recoveries were greater than 70%. The method was successfully applied to evaluate the effect of THP enantiomers on the activity of CYP450 isozymes by a cocktail approach. The pharmacokinetic results of five probe drugs indicated that there were stereoselective differences between the two THP enantiomers, i.e., d‐THP had the potential to inhibit the activities of CYP2D6 and CYP1A2 isozymes, while l‐THP inhibited CYP1A2 isozyme and induced CYP3A4 and CYP2C9 isozymes. Chirality 27:551–556, 2015. © 2015 Wiley Periodicals, Inc.     

Discovery of a novel series of selective HCN1 blockers

The discovery of a series of novel, potent, and selective blockers of the cyclic nucleotide-modulated channel HCN1 is disclosed. Here we report an SAR study around a series of selective blockers of the HCN1 channel. Utilization of a high-throughput VIPR assay led to the identification of a novel series of 2,2-disubstituted indane derivatives, which had moderate selectivity and potency at HCN1. Optimization of this hit led to the identification of the potent, 1,1-disubstituted cyclohexane HCN1 blocker, 2-ethoxy-N-((1-(4-isopropylpiperazin-1-yl)cyclohexyl)methyl)benzamide. The work leading to the discovery of this compound is described herein.     

Discovery of non-peptide, small molecule antagonists of α9α10 nicotinic acetylcholine receptors as novel analgesics for the treatment of neuropathic and tonic inflammatory pain

A series of azaaromatic quaternary ammonium analogs has been discovered as potent and selective α9α10 nicotinic acetylcholine receptor (nAChR) antagonists. The preliminary structure-activity relationships of these analogs suggest that increased rigidity in the linker units results in higher potency in inhibition of α9α10 nAChRs and greater selectivity over α7 nAChRs. These analogs represent a new class of analgesic for the treatment of neuropathic and tonic inflammatory pain.     

Methyl-monofluorination of ibuprofen selectively increases its inhibitory activity toward cyclooxygenase-1 leading to enhanced analgesic activity and reduced gastric damage in vivo

Newly developed monofluoromethylation reaction provided access to various bioactive molecules with an interesting monofluoromethyl unit. An iridium-catalyzed asymmetric version was employed for large-scale methyl-monofluorination of widely used nonsteroidal anti-inflammatory drug ibuprofen (the active S isoform). The methyl-monofluorinated ibuprofen was found to selectively inhibit cyclooxygenase-1 over cyclooxygenase-2 and surprisingly, the compound, with almost equal pharmacokinetic profile, was shown to increase analgesic activity and diminish gastric damage in animal models comparing to the parent drug ibuprofen. Therefore, methyl-monofluorination could be a useful strategy for improving efficacy and safety profile of drugs from the ‘profen’ family.     

DNA-dependent protein kinase (DNA-PK) inhibitors: structure-activity relationships for O-alkoxyphenylchromen-4-one probes of the ATP-binding domain

Introduction of an O-alkoxyphenyl substituent at the 8-position of the 2-morpholino-4H-chromen-4-one pharmacophore enabled regions of the ATP-binding site of DNA-dependent protein kinase (DNA-PK) to be probed further. Structure-activity relationships have been elucidated for inhibition of DNA-PK and PI3K (p110α), with N-(2-(cyclopropylmethoxy)-4-(2-morpholino-4-oxo-4H-chromen-8-yl)phenyl)-2-morpholinoacetamide 11a being identified as a potent and selective DNA-PK inhibitor (IC₅₀ = 8 nM).     

Synthesis and anti-inflammatory activity of some novel 3-phenyl-N-[3-(4-phenylpiperazin-1yl)propyl]-1H-pyrazole-5-carboxamide derivatives

A new series of 3-phenyl-N-[3-(4-phenylpiperazin-1yl)propyl]-1H-pyrazole-5-carboxamide derivatives were synthesized and investigated their anti-inflammatory activities using carrageenan-induced rat paw edema model in vivo. All the synthesized compounds were found to be potent anti-inflammatory agents.     

上海市某区社区卫生服务中心门诊用药合理性评价

利用6个合理用药国际指标以及TOPSIS法,综合分析和评价了2009年上海市某区12所社区卫生服务中心门诊用药状况。12种社区卫生服务中心门诊处方分析显示：平均药费为77.11元/张,平均药物数为2.30种,抗菌药物费用比例为12.02%,针剂费用比例为12.95%,抗菌药物处方比例为26.27%,国家基本药物使用比例为56.45%。根据C _i值分析,社区卫生服务中心的门诊用药基本合理,部分医疗机构门诊用药合理性有待提高。     

抗乙型肝炎病毒药物评价用实验动物模型现状

乙型肝炎病毒(HBV)感染严重影响人类的健康,感染HBV的慢性患者可引起肝硬化、肝细胞癌及肝功丧失等病症.开发有效的抗HBV药物,对于其感染的治疗非常关健.HBV具有非常窄的宿主范围,因此选择合适的药物评价用动物模型至关重要,常用的模型动物有鸭、土拔鼠、黑猩猩及近年研究的转基因小鼠等.