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Atropisomerism in the Pharmaceutically Relevant Realm
Accounts of Chemical Research ( IF 18.3 ) Pub Date : 2022-09-26 , DOI: 10.1021/acs.accounts.2c00500 Mariami Basilaia 1 , Matthew H Chen 1 , Jim Secka 1 , Jeffrey L Gustafson 1
Accounts of Chemical Research ( IF 18.3 ) Pub Date : 2022-09-26 , DOI: 10.1021/acs.accounts.2c00500 Mariami Basilaia 1 , Matthew H Chen 1 , Jim Secka 1 , Jeffrey L Gustafson 1
Affiliation
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.
中文翻译:
药学相关领域的阻转异构现象
阻转异构是一种构象手性,当围绕 σ 键的旋转受阻时发生。虽然阻转异构现象以联芳基化合物为例,但在许多其他药学相关支架中也观察到它,包括异联芳基化合物、苯甲酰胺、二芳基胺和苯胺。由于键旋转导致外消旋化,阻转异构体跨越了立体化学稳定性的范围。LaPlante 根据阻转异构体在 37 °C 时的外消旋半衰期进行了分类:1 类(t 1/2 < 60 s)、2 类(60 s < t 1/2 < 4.5 年)和 3 类(t 1 /2> 4.5 岁)。一般来说,3类阻转异构体被认为适合用于药物开发。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进行临床试验或最近出现在药物发现文献中。1 类阻转异构体更为普遍,近 30% 的 FDA 批准的小分子至少具有一个 1 类轴。虽然 1 类阻转异构体不具备必要的立体化学稳定性来满足阻转异构的经典定义,但它们通常以一组特定的手性构象结合给定的目标。
更新日期:2022-09-26
中文翻译:
药学相关领域的阻转异构现象
阻转异构是一种构象手性,当围绕 σ 键的旋转受阻时发生。虽然阻转异构现象以联芳基化合物为例,但在许多其他药学相关支架中也观察到它,包括异联芳基化合物、苯甲酰胺、二芳基胺和苯胺。由于键旋转导致外消旋化,阻转异构体跨越了立体化学稳定性的范围。LaPlante 根据阻转异构体在 37 °C 时的外消旋半衰期进行了分类:1 类(t 1/2 < 60 s)、2 类(60 s < t 1/2 < 4.5 年)和 3 类(t 1 /2> 4.5 岁)。一般来说,3类阻转异构体被认为适合用于药物开发。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进行临床试验或最近出现在药物发现文献中。1 类阻转异构体更为普遍,近 30% 的 FDA 批准的小分子至少具有一个 1 类轴。虽然 1 类阻转异构体不具备必要的立体化学稳定性来满足阻转异构的经典定义,但它们通常以一组特定的手性构象结合给定的目标。