Synthesis of functionalized derivatives of the gamma-secretase modulator BMS-932481 and identification of its major metabolite. Issue 22 (15th November 2020)

• Record Type: Journal Article
• Authors: Zhang, Yunhui; Boy, Kenneth M.; Wu, Yong-Jin; Ramirez, Antonio; Toyn, Jeremy H.; Ahlijanian, Michael K.; Albright, Charles F.; Zhuo, Xiaoliang; Johnson, Benjamin M.; Denton, R. Rex; Olson, Richard E.; Thompson, Lorin A.; Macor, John E.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 22(2020)
• Publication Date: 2020-11-15
• Subjects: Alzheimer's disease -- GS modulators -- Metabolites; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127530
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: In an effort to improve physical properties by introducing polar functionality into the bicyclic pyrimidine gamma-secretase modulator (GSM) clinical candidate BMS-932481, we prepared several oxidative products of BMS-932481. Among the analogs that were prepared, the C-5 alcohol 3 was identified as the predominant metabolite of BMS-932481 found in rat and human liver microsomes. Alcohol 3 was determined to be chemically unstable, leading to the hypothesis that 3 may lead to the production of reactive species both in vitro and in vivo .