Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)pyridinyl‑1H‑benzimidazole Diacylglycerol Acyltransferase 1 Inhibitors

Miniaturization and parallel processing play an important role in the evolution of many technologies. We demonstrate the application of miniaturized high-throughput experimentation methods to resolve synthetic chemistry challenges on the frontlines of a lead optimization effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors. Reactions were performed on ∼1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging SNAr reaction. The availability of robust synthetic chemistry conditions discovered in these miniaturized investigations enabled the development of structure–activity relationships that ultimately led to the discovery of soluble, selective, and potent inhibitors of DGAT1.微型化与并行处理在众多技术的演进历程中扮演着至关重要的角色。本研究将微型化高通量实验方法应用于二酰基甘油酰基转移酶（DGAT1）抑制剂开发的先导优化一线工作，以解决其中的合成化学难题。实验采用玻璃微量瓶在约1毫克的反应规模下开展，搭建了微型化高通量实验平台，用于研究极具挑战性的亲核芳香取代（SNAr）反应。通过本次微型化研究所发掘的稳定合成反应条件，得以构建构效关系，最终发现了兼具可溶性、选择性与强效活性的DGAT1抑制剂。