Medicinal Chemistry and ‡Modeling and Informatics, Alkermes, Plc , 852 Winter Street, Waltham, Massachusetts 02451-1420, United States.
J Med Chem. 2017 May 11;60(9):3552-3579. doi: 10.1021/acs.jmedchem.6b01807. Epub 2017 Feb 8.
There is a continued desire in biomedical research to reduce the number and duration of design cycles required to optimize lead compounds into high-quality chemical probes or safe and efficacious drug candidates. The insightful application of impactful molecular design elements is one approach toward achieving this goal. The replacement of a CH group with a N atom in aromatic and heteroaromatic ring systems can have many important effects on molecular and physicochemical properties and intra- and intermolecular interactions that can translate to improved pharmacological profiles. In this Perspective, the "necessary nitrogen atom" is shown to be a versatile high-impact design element for multiparameter optimization, wherein ≥10-, 100-, or 1000-fold improvement in a variety of key pharmacological parameters can be realized.
在生物医学研究中，人们一直希望减少优化先导化合物成为高质量化学探针或安全有效的候选药物所需的设计周期的数量和时长。有见地的应用有影响力的分子设计元素是实现这一目标的一种方法。在芳香族和杂环系统中，用氮原子取代 CH 基团可以对分子和物理化学性质以及分子内和分子间相互作用产生许多重要影响，从而改善药理学特性。在本观点中，“必需的氮原子”被证明是多参数优化的多功能高影响力设计元素，其中可以实现多种关键药理学参数提高 10 倍、100 倍或 1000 倍以上。
