Nitrile-containing pharmaceuticals: efficacious roles of the nitrile pharmacophore.
Nitrile-containing pharmaceuticals: efficacious roles of the nitrile pharmacophore.
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DOI：
10.1021/jm100762r
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发表时间：
2010-11-25
影响因子：
7.3
通讯作者：
Shook BC
中科院分区：
文献类型：
--
作者：
Fleming FF;Yao L;Ravikumar PC;Funk L;Shook BC
超过30种含腈药物被用于各种各样的医学适应症，另外还有20多种含腈药物正在临床开发中。随着含腈药物数量的增加，确定腈在医疗制剂中作用的趋势已经出现。与越来越多的含腈试剂相结合的是结构上的进步，这些进步提供了对小分子抑制剂结合的深入了解。特别是X射线晶体学通过越来越多的结构与活性位点结合的抑制剂提供了对小分子-蛋白质相互作用的关键见解。增加与当前含腈药物的可用相互作用的细节来自不再开发的临床候选药物。本审查调查这一范围内的药用活性腈通过集中在CN单元的作用，含腈的药物和潜在的代理人在临床上的持续流的患病率证明了腈官能团的生物相容性。1腈基对游离的亲核体（甚至谷胱甘肽）并不特别亲电，2除非被相邻的结构元素（如吸电子基团）激活。3需要注意的是高度协调的活化亲电加成，例如在用于糖尿病和骨质疏松症治疗的几种氨基腈中开发的那些，其特征是可逆的亲电攻击（见下文）。腈基非常坚固，在大多数情况下不易代谢。4在代谢上，大多数含腈药物中的腈基在体内是不变的。5在消除前药物代谢的情况下，葡萄糖醛酸苷的形成、6与谷胱甘肽的结合、7 N-脱烷基化、8 N-乙酰化、9水解、6a-d和氧化10通常发生在远离腈的位点，而腈基没有修饰。
Over 30 nitrile-containing pharmaceuticals are prescribed for a diverse variety of medicinal indications with more than 20 additional nitrile-containing leads in clinical development. Trends identifying the roles of the nitrile in medical agents have emerged as the number of nitrile-containing pharmaceuticals has increased. Coupled with the increasing number of nitrile-containing agents have been structural advances that provide insight into the binding of small molecule inhibitors. X-ray crystallography in particular is providing key insight into small molecule-protein interactions through an increasing number of structures with inhibitors bound in the active site. Augmenting the available interactions with current nitrilecontaining pharmaceuticals are details from clinical candidates no longer under development. The present review surveys this range of medicinally active nitriles by focusing on the roles of the CN unit.The prevalence of nitrile-containing pharmaceuticals and the continued stream of potential agents in the clinic attest to the biocompatibility of the nitrile functionality. 1 The nitrile group is not particularly electrophilic toward free nucleophiles, even glutathione, 2 unless activated by adjacent structural elements such as electron withdrawing groups. 3 A caveat is the highly orchestrated activation-electrophilic additions such as those being exploited in several aminonitriles for diabetes and osteoporosis treatments that feature a reversible electrophilic attack (vide infra). The nitrile group is quite robust and, in most cases, is not readily metabolized. 4 Metabolically, the nitrile group in most nitrile-containing drugs is passed through the body unchanged. 5 In cases of drug metabolism prior to elimination, the formation of glucuronides, 6 conjugation with glutathione, 7 N-dealkylation, 8 N-acetylation, 9 hydrolysis, 6a-d and oxidation10 typically occurs at sites remote from the nitrile and without modification of the nitrile group.
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影响因子：
7.3
作者：
BERGMANN, R;GERICKE, R
通讯作者：
GERICKE, R
影响因子：
2.7
作者：
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影响因子：
7.3
作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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