Atropisomerism in the Pharmaceutically Relevant Realm.
Atropisomerism in the Pharmaceutically Relevant Realm.
复制标题
DOI：
10.1021/acs.accounts.2c00500
复制
发表时间：
2022-10-18
影响因子：
18.3
通讯作者：
Gustafson, Jeffrey L.
中科院分区：
文献类型：
--
作者：
Basilaia, Mariami;Chen, Matthew H.;Secka, Jim;Gustafson, Jeffrey L.
阻转异构是当围绕σ键存在受阻旋转时发生的构象手性。虽然阻转异构性以联芳基为例，但在许多其他药学相关的支架中也观察到阻转异构性，包括杂联芳基、苯甲酰胺、二芳基胺和苯胺。由于键旋转导致外消旋化，阻转异构体跨越立体化学稳定性的范围。LaPlante根据阻转异构体在37 °C下的外消旋半衰期将其分类为：1类（t1/2 < 60 s）、2类（60 s < t1/2 < 4.5年）和3类（t1/2 > 4.5年）。一般而言，认为3类阻转异构体适用于药物开发。目前有四种FDA批准的药物作为稳定的阻转异构体存在，还有许多其他药物正在临床试验中或最近出现在药物发现文献中。1类阻转异构体更普遍，最近FDA批准的小分子中约有30%具有至少一个1类轴。虽然1类阻转异构体不具有满足阻转异构的经典定义所需的立体化学稳定性，但它们通常以特定的手性构象结合给定的靶标。在过去的十年中，我们的实验室已经开始了一项研究计划，旨在利用阻转异构作为一个设计特征，以提高目标选择性的混杂铅化合物。我们的研究最初集中在将3类阻转异构体引入混杂激酶抑制剂中，从而证明了一种原理，其中化合物的不同阻转异构体可以具有不同的选择性特征，并具有潜在的改进的靶标选择性。这激发了对与不同靶蛋白结合的不同配体的结合构象的仔细分析，从而实现了关于预期阻转异构体轴的采样二面角构象在靶结合中发挥了关键作用，并且将预期阻转异构体轴预组织成所需靶的优选构象范围可以导致靶选择性的大增益。随着阻转异构现象在现代药物发现中变得越来越普遍，对药物化合物的阻转异构纯样品的策略的需求日益增加。这使得我们和其他研究小组开发了催化性选择性方法，用于药物特许支架。我们的实验室已经贡献了对heterobiaryl系统的阻转选择性方法的例子，同时也探索了研究较少的阻转异构体，如二芳基胺和相关支架的手性。这个帐户将详细介绍最近遇到的阻转异构体在药物化学和阻转异构体如何从一个“潜伏的威胁”转变为一个可回收的设计策略，以调节生物活性小分子的各种特性。该帐户还将讨论atroposelective合成的最新进展，重点是对药物特许支架的方法。我们预测，更好地了解构象限制的影响有关的前瞻性阻转异构体轴对目标结合将使化学家能够快速“编程”的选择性的铅分子对所需的目标。
Atropisomerism is a conformational chirality that occurs when there is hindered rotation about a σ-bond. While atropisomerism is exemplified by biaryls, it is observed in many other pharmaceutically relevant scaffolds including heterobiaryls, benzamides, diarylamines, and anilides. As bond rotation leads to racemization, atropisomers span the gamut of stereochemical stability. LaPlante has classified atropisomers based on their half-life of racemization at 37 °C: class 1 (t1/2 < 60 s), class 2 (60 s < t1/2 < 4.5 years), and class 3 (t1/2 > 4.5 years). In general, class-3 atropisomers are considered to be suitable for drug development. There are currently four FDA-approved drugs that exist as stable atropisomers, and many others are in clinical trials or have recently appeared in the drug discovery literature. Class-1 atropisomers are more prevalent, with ∼30% of recent FDA-approved small molecules possessing at least one class-1 axis. While class-1 atropisomers do not possess the requisite stereochemical stability to meet the classical definition of atropisomerism, they often bind a given target in a specific set of chiral conformations. Over the past decade, our laboratory has embarked on a research program aimed at leveraging atropisomerism as a design feature to improve the target selectivity of promiscuous lead compounds. Our studies initially focused on introducing class-3 atropisomerism into promiscuous kinase inhibitors, resulting in a proof of principle in which the different atropisomers of a compound can have different selectivity profiles with potentially improved target selectivity. This inspired a careful analysis of the binding conformations of diverse ligands bound to different target proteins, resulting in the realization that the sampled dihedral conformations about a prospective atropisomeric axis played a key role in target binding and that preorganizing the prospective atropisomeric axis into a desired target’s preferred conformational range can lead to large gains in target selectivity. As atropisomerism is becoming more prevalent in modern drug discovery, there is an increasing need for strategies for atropisomerically pure samples of pharmaceutical compounds. This has led us and other groups to develop catalytic atroposelective methodologies toward pharmaceutically privileged scaffolds. Our laboratory has contributed examples of atroposelective methodologies toward heterobiaryl systems while also exploring the chirality of less-studied atropisomers such as diarylamines and related scaffolds. This Account will detail recent encounters with atropisomerism in medicinal chemistry and how atropisomerism has transitioned from a “lurking menace” into a leverageable design strategy in order to modulate various properties of biologically active small molecules. This Account will also discuss recent advances in atroposelective synthesis, with a focus on methodologies toward pharmaceutically privileged scaffolds. We predict that a better understanding of the effects of conformational restriction about a prospective atropisomeric axis on target binding will empower chemists to rapidly “program” the selectivity of a lead molecule toward a desired target.
登录
查看更多内容
影响因子：
5.2
作者：
Cardenas MM;Toenjes ST;Nalbandian CJ;Gustafson JL
通讯作者：
Gustafson JL
DOI：
10.1126/science.1188403
发表时间：
2010-06-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gustafson JL;Lim D;Miller SJ
通讯作者：
Miller SJ
影响因子：
15
作者：
Kitagawa, O;Takahashi, M;Taguchi, T
通讯作者：
Taguchi, T
影响因子：
3.6
作者：
Kazim, Muhammad;Siegler, Maxime A.;Lectka, Thomas
通讯作者：
Lectka, Thomas
影响因子：
7.3
作者：
Brow, Dean G.;Bostrom, Jonas
通讯作者：
Bostrom, Jonas