Synthesis of Functionalized Derivatives of the Gamma-Secretase Modulator BMS-932481 and Identification of its Major Metabolite.

Synthesis of Functionalized Derivatives of the Gamma-Secretase Modulator BMS-932481 and Identification of its Major Metabolite.
Bioorg Med Chem Lett. 2020 Sep 02;:127530
Authors: Zhang Y, Boy KM, Wu YJ, Ramirez A, Toyn JH, Ahlijanian MK, Albright CF, Zhuo X, Johnson BM, Denton RR, Olson RE, Thompson LA, Macor JE
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.
PMID: 32890687 [PubMed - as supplied by publisher]

Source: Bioorganic and Medicinal Chemistry Letters - September 1, 2020 Category: Chemistry Authors: Zhang Y, Boy KM, Wu YJ, Ramirez A, Toyn JH, Ahlijanian MK, Albright CF, Zhuo X, Johnson BM, Denton RR, Olson RE, Thompson LA, Macor JE Tags: Bioorg Med Chem Lett Source Type: research