Identification, synthesis and characterization of a unique N-glucuronide of an acid metabolite of camizestrant (AZD9833) in humans
This paper describes a novel hybrid chemical and biological synthetic route for making a major circulating indirect N-glucuronide (M14) of an acid metabolite (M46) of camizestrant (AZD9833). A novel hybrid chemical and biological synthetic route was developed to successfully synthesize M14, enabling further biological studies.
Abstract
Camizestrant (AZD9833) is a next generation oral selective estrogen receptor degrader and complete ER antagonist in Phase 3 clinical development for the treatment of ER-positive breast cancer. Metabolite M14, an N-glucuronide of the acid metabolite M46 of camizestrant, is one of the major circulating metabolites in humans, in addition to a direct N-glucuronide M4. In light of the fact that existence of the acidic functional group of the acid metabolite M46 prevented an efficient in vitro glucuronidation in human liver microsomes, a novel hybrid chemical and biological synthesis of AZ4678 (M14) was successfully achieved. The acidic functional group of AZ8713 (M46) was esterified with methanol to give the M46 methyl ester, which was then glucuronidated in human liver microsomes in the presence of UPDGA to form M14 methyl ester. Selective hydrolysis of M14 methyl ester by aqueous lithium hydroxide in THF successfully generated AZ4678 (M14). The development of this synthesis route has introduced a new approach to synthesizing glucuronides of compounds with acidic functional groups that otherwise interfere with their susceptibility to glucuronidation. NMR analysis confirmed the structure of AZ4678 (M14) with the glucuronic acid attached to the position N45 of the azole nitrogen atom while retaining the original stereochemistry of camizestrant. Chromatography of AZ4678 (M14) was sensitive to 67% of organic content in samples as well as sensitive to solvents at a basic pH containing ammonium hydroxide, resulting in split peaks in LCMS analysis. AZ4678 (M14) was stable in human feces and in aqueous solutions at a pH range of 1.5 to 12.0.
Paper
Identification, synthesis and characterization of a unique N-glucuronide of an acid metabolite of camizestrant (AZD9833) in humans.
Zhoupeng Zhang, Stephen Wilkinson, Peter W.A. Howe, April Chen, Richard Phipps, Andy Sykes, Lâm Quang Tran, Emily Hopkins, Guy Brenchley, Niresh Hariparsad,
Drug Metabolism and Disposition, 2026, 100249, ISSN 0090-9556, https://doi.org/10.1016/j.dmd.2026.100249.