Schofield Kevin, Maddern Shayna, Zhang Yueteng, Mastin Grace E, Knight Rachel, Wang Wei, Galligan James, Hulme Christopher
Department of Chemistry and Biochemistry, College of Science, University of Arizona, Tucson, Arizona, 85721, USA.
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona, 85721, USA.
Beilstein J Org Chem. 2024 Sep 6;20:2270-2279. doi: 10.3762/bjoc.20.195. eCollection 2024.
The utility of bio-isosteres is broad in drug discovery and methodology herein enables the preparation of deuterium-labeled products is the most fundamental of known bio-isosteric replacements. As such we report the use of both [D]-aldehydes and [D]-isonitriles across 8 multicomponent reactions (MCRs) to give diverse arrays of deuterated products. A highlight is the synthesis of several FDA-approved calcium channel blockers, selectively deuterated at a limiting metabolic soft-spot via use of [D]-aldehydes. Surrogate pharmacokinetic analyses of microsomal stability confirm prolongation of of the new deuterated analogs. We also report the first preparation of [D]-isonitriles from [D]-formamides via a modified Leuckart-Wallach reaction and their use in an MCR to afford products with [D]-benzylic positions and likely significantly enhanced metabolic stability, a key parameter for property-based design efforts.
生物电子等排体在药物发现中的应用广泛，本文所介绍的方法能够制备氘代产物，这是已知生物电子等排体替代中最基本的。因此，我们报道了使用[D]-醛和[D]-异腈参与8种多组分反应（MCRs），以得到各种氘代产物。一个亮点是合成了几种FDA批准的钙通道阻滞剂，通过使用[D]-醛在一个有限的代谢软点处进行选择性氘代。微粒体稳定性的替代药代动力学分析证实了新的氘代类似物的半衰期延长。我们还报道了通过改良的Leuckart-Wallach反应首次从[D]-甲酰胺制备[D]-异腈，并将其用于MCR中，以得到具有[D]-苄基位置且可能显著提高代谢稳定性的产物，这是基于性质的设计工作的一个关键参数。
