In 2022,Zhao, Zean; Liu, Jin; Kuang, Peihua; Luo, Jian; Surineni, Goverdhan; Cen, Xiaolin; Wu, Ting; Cao, Ying; Zhou, Pingzheng; Pang, Jianxin; Zhang, Qun; Chen, Jianjun published an article in European Journal of Medicinal Chemistry. The title of the article was 《Discovery of novel verinurad analogs as dual inhibitors of URAT1 and GLUT9 with improved Druggability for the treatment of hyperuricemia》.SDS of cas: 1129-28-8 The author mentioned the following in the article:
Verinurad (RDEA3170) is a selective URAT1 inhibitor under investigation for the treatment of gout and hyperuricemia. In an effort to further improve the pharmacodynamics/pharmacokinetics of verinurad and to increase the structural diversity, we designed novel verinurad analogs by introducing a linker (e.g. aminomethyl, amino or oxygen) between the naphthalene and the pyridine ring to increase the flexibility. These compounds were synthesized and tested for their in vitro URAT1-inhibitory activity. Most compounds exhibited potent inhibitory activities against URAT1 with IC50 values ranging from 0.24 μM to 16.35 μM. Among them, compound KPH2f exhibited the highest URAT1-inhibitory activity with IC50 of 0.24 μM, comparable to that of verinurad (IC50 = 0.17 μM). KPH2f also inhibited GLUT9 with an IC50 value of 9.37 ± 7.10 μM, indicating the dual URAT1/GLUT9 targeting capability. In addition, KPH2f showed little effects on OAT1 and ABCG2, and thus was unlikely to cause OAT1/ABCG2-mediated drug-drug interactions and/or to neutralize the uricosuric effects of URAT1/GLUT9 inhibitors. Importantly, KPH2f (10 mg/kg) was equally effective in reducing serum uric acid levels and exhibited higher uricosuric effects in a mice hyperuricemia model, as compared to verinurad (10 mg/kg). Furthermore, KPH2f demonstrated favorable pharmacokinetic properties with an oral bioavailability of 30.13%, clearly better than that of verinurad (21.47%). Moreover, KPH2f presented benign safety profiles without causing hERG toxicity, cytotoxicity in vitro (lower than verinurad), and renal damage in vivo. Collectively, these results suggest that KPH2f represents a novel, safe and effective dual URAT1/GLUT9 inhibitor with improved druggabilities and is worthy of further investigation as an anti-hyperuricemic drug candidate. The results came from multiple reactions, including the reaction of Methyl 3-(bromomethyl)benzoate(cas: 1129-28-8SDS of cas: 1129-28-8)
Methyl 3-(bromomethyl)benzoate(cas: 1129-28-8) belongs to organobromine compounds.Most of the natural organobromine compounds are produced by marine organisms , and several brominated metabolites with antibacterial , antitumor , antiviral , and antifungal activity have been isolated from seaweed, sponges, corals, molluscs, and others. SDS of cas: 1129-28-8 Moreover, several studies demonstrate that the average proportion of bromine in drugs is significantly higher than that in natural products.
Referemce:
Bromide – Wikipedia,
bromide – Wiktionary