碳酸酐酶抑制剂药物化学的最新进展,European Journal of Medicinal Chemistry

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碳酸酐酶抑制剂药物化学的最新进展,European Journal of Medicinal Chemistry

2024-07-08 23:10| 来源: 网络整理| 查看: 265

碳酸酐酶(CA,EC 4.2.1.1)是一种酶和一种非常普遍的锌金属酶,它催化二氧化碳和碳酸氢盐的可逆水合和脱水。在许多生理和病理过程中起关键作用的反应。碳酸酐酶以十六种不同的异构体形式存在于人(人类)中,形式从hCA I-hCA XV不等。所有这些同工型广泛分布在不同的组织/器官中,并与一系列关键的生理活动有关。由于它们参与各种生理作用,碳酸酐酶的不同人类同工型的抑制剂已发现用于治疗包括青光眼,视网膜病变,溶血性贫血,癫痫,肥胖症和癌症在内的各种疾病的临床应用。但是,临床上使用的CA抑制剂(乙酰唑胺,布林酰胺,多佐胺等)没有选择性,导致不良的副作用。碳酸酐酶抑制剂设计和开发的主要障碍之一是缺乏平衡的异构体选择性,该异构体选择性已发展为新的化学型。在这篇综述中,我们汇总了与碳酸酐酶抑制剂的发展有关的各种研究人员的最新策略,这些碳酸酐酶抑制剂属于嘧啶,吡唑啉,硒硒,靛红,吲哚等不同结构类别。该综述还总结了结构-活性关系,分析异构体选择性包括机理和在计算机研究中提供思想,并为设计和开发具有治疗意义的新型同工型选择性碳酸酐酶抑制剂提供重点指导。

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Recent advances in the medicinal chemistry of carbonic anhydrase inhibitors

Carbonic anhydrase (CA, EC 4.2.1.1) is an enzyme and a very omnipresent zinc metalloenzyme which catalyzed the reversible hydration and dehydration of carbon dioxide and bicarbonate; a reaction which plays a crucial role in many physiological and pathological processes. Carbonic anhydrase is present in human (h) with sixteen different isoforms ranging from hCA I-hCA XV. All these isoforms are widely distributed in different tissues/organs and are associated with a range of pivotal physiological activities. Due to their involvement in various physiological roles, inhibitors of different human isoforms of carbonic anhydrase have found clinical applications for the treatment of various diseases including glaucoma, retinopathy, hemolytic anemia, epilepsy, obesity, and cancer. However, clinically used inhibitors of CA (acetazolamide, brinzolamide, dorzolamide, etc.) are not selective causing the undesirable side effects. One of the major hurdles in the design and development of carbonic anhydrase inhibitors is the lack of balanced isoform selectivity which thrived to new chemotypes. In this review, we have compiled the recent strategies of various researchers related to the development of carbonic anhydrase inhibitors belonging to different structural classes like pyrimidine, pyrazoline, selenourea, isatin, indole, etc. This review also summarizes the structure-activity relationships, analysis of isoform selectivity including mechanistic and in silico studies to afford ideas and to provide focused direction for the design and development of novel isoform-selective carbonic anhydrase inhibitors with therapeutic implications.



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