Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Department of Chemistry and Biochemistry, Montana State University, 103 Chemistry and Biochemistry, Bozeman, Montana 59717, USA.
Bioorg Chem. 2022 Nov;128:106074. doi: 10.1016/j.bioorg.2022.106074. Epub 2022 Aug 12.
The imidazo[1,2-a]pyridine-3-carboxyamides (IAPs) are a unique class of compounds endowed with impressive nanomolar in vitro potency against Mycobacterium tuberculosis (Mtb) as exemplified by clinical candidate Telacebec (Q203). These compounds target mycobacterial respiration through inhibition of the QcrB subunit of cytochrome bc1:aa super complex resulting in bacteriostatic efficacy in vivo. Our labs have had a long-standing interest in the design and development of IAPs. However, some of these compounds suffer from short in vivo half-lives, requiring multiple daily dosing or the addition of a cytochrome P450 inhibitor for murine efficacy evaluations. Deuteration has been shown to decrease metabolism as the C-D bond is stronger than the CH bond. Herein we describe our efforts on design and synthesis of potent deuterated IAPs and the effect that deuteration has upon metabolism through microsomal stability studies.
咪唑并[1,2-a]吡啶-3-甲酰胺（IAPs）是一类具有独特结构的化合物，对结核分枝杆菌（Mtb）具有令人印象深刻的纳摩尔体外活性，临床候选药物 Telacebec（Q203）就是一个很好的例子。这些化合物通过抑制细胞色素 bc1:aa 超复合体的 QcrB 亚基来靶向分枝杆菌呼吸，从而在体内产生抑菌效果。我们实验室一直对 IAPs 的设计和开发感兴趣。然而，其中一些化合物在体内的半衰期较短，需要每天多次给药，或者需要添加细胞色素 P450 抑制剂才能在小鼠中进行疗效评估。氘代已被证明可以降低代谢，因为 C-D 键比 CH 键更强。本文描述了我们在设计和合成有效氘代 IAPs 方面的努力，以及氘代对通过微粒体稳定性研究代谢的影响。
