Discovery of substituted lactams as novel dual orexin receptor antagonists. Synthesis, preliminary structure-activity relationship studies and efforts towards improved metabolic stability and pharmacokinetic properties. Part 1
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- 作者：Thierry Sifferlen ; Am ; ine Boller ; Audrey Chardonneau ; Emmanuelle Cottreel ; Johannes Hoecker ; Hamed Aissaoui ; Jodi T. Williams ; Christine Brotschi ; Bibia Heidmann ; Romain Siegrist ; John Gatfield ; Alex ; er Treiber ; Catherine Brisbare-Roch ; Francois Jenck ; Christoph Boss
- 关键词：G-protein coupled receptors ; Orexin antagonists ; CNS drug discovery ; Metabolic stability ; Structure&ndash ; activity relationship studies
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：15 February, 2014
- 年：2014
- 卷：24
- 期：4
- 页码：1201-1208
- 全文大小：951 K
文摘
Starting from a thiazolidin-4-one HTS hit, a novel series of substituted lactams was identified and developed as dual orexin receptor antagonists. In this Letter, we describe our initial efforts towards the improvement of potency and metabolic stability. These investigations delivered optimized lead compounds with CNS drug-like properties suitable for further optimization.