Synthesis and In Vitro Metabolic Profiling of the Selective Androgen Receptor Modulator (SARM) LY305.

Area of Science:

• Pharmacology
• Biochemistry
• Analytical Chemistry

Background:

• Selective androgen receptor modulators (SARMs) like LY305 are investigated for therapeutic potential in muscle wasting and hypogonadism.
• The anabolic effects of LY305 necessitate understanding its metabolism for anti-doping efforts.
• Information on LY305 biotransformation is crucial for developing targeted doping control analyses.

Purpose of the Study:

• To synthesize 2-Chloro-4-[[(1R,2R)-2-hydroxy-2-methyl-cyclopentyl]amino]-3-methyl-benzonitrile (LY305).
• To investigate the in vitro metabolic profile of LY305 using human liver microsomes and S9 fractions.
• To identify phase-I and phase-II metabolites of LY305 for anti-doping applications.

Main Methods:

• Synthesis of LY305 via Buchwald-Hartwig amination.
• In vitro metabolism studies utilizing human liver microsomes (HLM) and S9 fractions.
• Analysis of LY305 and its metabolites using liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS).

Main Results:

• Successful synthesis of LY305.
• Detection of 18 metabolites, including nine phase-I and nine phase-II conjugates.
• Identification of metabolic pathways: hydroxylation, dehydrogenation, oxidation, O-glucuronidation, and combinations thereof.

Conclusions:

• The synthesis and in vitro metabolic profiling of LY305 were achieved.
• Generated chromatographic and mass spectral data can enhance anti-doping detection methods.
• This study provides the first reported in vitro metabolic data for LY305, supporting its potential clinical evaluation and anti-doping surveillance.