Chlorotrimethylsilane promoted one-flask heterocyclic synthesis of 1,2,4-triazoles from nitrilimines: Modeling studies and bioactivity evaluation of LH-21 and Rimonabant analogues

2区 · 化学

Article

作者: Chung, Cheng-Yen ; Chieh Lin, Chun ; Tsai, Shuo-En ; Yang, Li-Chan ; Wong, Fung-Fuh ; Zeng, Yu-Hui ; Fuh, Mao-Tsu ; Yang, Ya-Chen ; Li, Sin-Min ; Tseng, Ching-Chun

An efficient one-flask cascade method for synthesis of the multi-substituted 1,2,4-triazoles via chlorotrimethylsilane as a promoter was developed. Firstly, nitrilimines were transformed to hydrazonamides as intermediate in high yield by treatment with commercially available hexamethyldisilazane. Subsequently, the mixture was added with corresponding acyl chloride and heated in the presence of pyridine to give the corresponding multi-substituted 1,2,4-triazoles via chlorotrimethylsilane promoted heterocyclization reaction. The utility of method was demonstrated to synthesize CB₁ ligands including Rimonabant analogue 4c and LH-21 3 for modeling study. All synthesized compounds were subjected to the cAMP functional assay of CB₁/CB₂ receptor. Especially, compound 4g enhanced the reversal of cAMP reduction by CP59440 than LH-21 and Rimonabant analogue in CHO-hCB₁ cells. In addition, the docking results showed compound 4g fits the best position with CB₁ receptor. However, the ability to penetrate brain-blood barrier of compound 4g is similar with Rimonabant in MDCK-mdr1 permeability assay, which might cause CNS side effect. This study still provides the basis for further development of a potent and specific CB₁ antagonist.

2018-05-28·Pharmaceutical Development and Technology4区 · 医学

Understanding the compaction behaviour of low-substituted HPC: macro, micro, and nano-metric evaluations

4区 · 医学

Article

作者: Al-khattawi, Ali ; ElShaer, Amr ; Mohammed, Afzal R. ; Warzecha, Monika ; Lamprou, Dimitrios A. ; Hassanin, Hany

The fast development in materials science has resulted in the emergence of new pharmaceutical materials with superior physical and mechanical properties. Low-substituted hydroxypropyl cellulose is an ether derivative of cellulose and is praised for its multi-functionality as a binder, disintegrant, film coating agent and as a suitable material for medical dressings. Nevertheless, very little is known about the compaction behaviour of this polymer. The aim of the current study was to evaluate the compaction and disintegration behaviour of four grades of L-HPC namely; LH32, LH21, LH11, and LHB1. The macrometric properties of the four powders were studied and the compaction behaviour was evaluated using the out-of-die method. LH11 and LH22 showed poor flow properties as the powders were dominated by fibrous particles with high aspect ratios, which reduced the powder flow. LH32 showed a weak compressibility profile and demonstrated a large elastic region, making it harder for this polymer to deform plastically. These findings are supported by AFM which revealed the high roughness of LH32 powder (100.09 ± 18.84 nm), resulting in small area of contact, but promoting mechanical interlocking. On the contrary, LH21 and LH11 powders had smooth surfaces which enabled larger contact area and higher adhesion forces of 21.01 ± 11.35 nN and 9.50 ± 5.78 nN, respectively. This promoted bond formation during compression as LH21 and LH11 powders had low strength yield.

2017-08-01·Pharmacology Biochemistry and Behavior4区 · 心理学

Pharmacological comparison of traditional and non-traditional cannabinoid receptor 1 blockers in rodent models in vivo

4区 · 心理学

Article

作者: Fischer, János ; Kovács, Péter ; Kassai, Ferenc ; Varga, Balázs ; Gyertyán, István ; Szabó, György

Cannabinoid receptor 1 (CB1R) antagonists have been proven to be effective anti-obesity drugs; however, psychiatric side effects have halted their pharmaceutical development worldwide. Despite the emergence of next generation CB1R blockers, a preclinical head to head comparison of the anti-obesity and psychiatric side effect profiles of the key compounds has not been performed. Here, we compared classical CB1R antagonists (rimonabant, taranabant, otenabant, ibipinabant, and surinabant) and non-traditional CB1R blockers (the partial agonist O-1269, the neutral antagonists VCHSR and LH-21 and the peripherally acting inverse agonist JD-5037) using an in vivo screening cascade. First, the potencies of these compounds to reduce CB1R agonist-induced hypothermia and decrease fasting-induced food intake were determined. Then, equipotent doses of the non-toxic compounds were compared in a diet-induced obesity (DIO) test, which includes measurements of metabolic syndrome markers. Psychiatric side effects were assessed by measuring anxiogenicity in an ultrasonic vocalization test. All classical CB1R blockers were centrally acting appetite suppressants and decreased body weight and food intake in an obesity-dependent manner, with only slight effects on metabolic syndrome markers. In addition, all classical CB1R blockers increased ultrasonic vocalization. Surprisingly, none of the non-classical CB1R blockers was eligible for the DIO comparison and side effect profiling. O-1269 and LH-21 induced convulsive behavior, whereas VCHSR and JD-5037 were devoid of any in vivo activity. The classical CB1R blockers displayed similar therapeutic and side effect profiles in vivo, whereas the available non-traditional CB1R blockers were not appropriate tools for testing the therapeutic potential of alternative CB1R inhibitors.

100 项与 LH-021 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
膝关节炎	临床1期	中国	广州领晟医疗科技有限公司	2019-12-17
软骨损伤	临床申请批准	中国	广州领晟医疗科技有限公司	2022-12-29