Centre for Neuroscience Research, Faculty of Medicine, Universiti Teknologi MARA, Malaysia.
Centre for Neuroscience Research, Faculty of Medicine, Universiti Teknologi MARA, Malaysia; Volgograd State Medical University, Research Institute of Pharmacology, Volgograd, Russia.
Eur J Pharm Sci. 2018 Mar 1;114:245-254. doi: 10.1016/j.ejps.2017.12.015. Epub 2017 Dec 21.
In an effort to find new ocular hypotensive drug candidates, a total of 27 condensed benzimidazoles based compounds were screened. This study was done in normotensive rats and rebound tonometry was used to estimate IOP. All compounds were topically applied as a single drop, unilaterally, at 3 different concentrations (0.1%, 0.2% and 0.4%). The contralateral eye was instilled with vehicle and served as control. The IOP reduction was measured up to 6h. It was observed that with a single topical instillation, compounds RU 551, RU 555, RU839 (pyrimido[1,2-a]benzimidazole derivatives), and RU 615 (imidazo[1,2-a]benzimidazole derivative) showed significant IOP lowering activities in ocular normotensive rats. All other compounds showed none, weak and inconsistent IOP lowering effect. The relationship between ability of IOP lowering and hypotensive activities was studied. According to the pharmacophore analysis, the class of pyrimido[1,2-a]benzimidazole is more promising than the class of imidazo[1,2-a]benzimidazole as a source of compounds with high IOP lowering activity. Pharmacophore analysis also showed that the critical features of high IOP lowering activity are methoxyphenyl and [phenyl]alkyl fragments, and non-conjugated six-membered heterocyclic ring.
为了寻找新的降眼压药物候选物，我们筛选了总共 27 种浓缩苯并咪唑类化合物。这项研究是在正常血压大鼠中进行的，使用回弹眼压计来估计眼压。所有化合物均以单滴形式局部应用，单侧使用 3 种不同浓度（0.1％、0.2％和 0.4％）。对侧眼滴注载体作为对照。测量眼压降低至 6 小时。结果观察到，单次局部滴眼后，化合物 RU 551、RU 555、RU839（嘧啶并[1,2-a]苯并咪唑衍生物）和 RU 615（咪唑并[1,2-a]苯并咪唑衍生物）在正常眼压大鼠中表现出显著的降眼压活性。其他所有化合物均无、弱且不一致的降眼压作用。研究了降眼压能力与降压活性之间的关系。根据药效基团分析，嘧啶并[1,2-a]苯并咪唑类化合物比咪唑并[1,2-a]苯并咪唑类化合物更有希望成为具有高降眼压活性的化合物的来源。药效基团分析还表明，高降眼压活性的关键特征是甲氧基苯基和[苯基]烷基片段，以及非共轭六元杂环。
