The development of non-steroidal selective androgen receptor modulators (SARMs) offers potentially beneficial androgen-dependent effects in a tissue-selective manner, while avoiding unwanted androgenic effects observed with steroidal agents. SARMs are not substrates for metabolic conversion to dihydrotestosterone or estradiol, thus limiting the potential for development of benign prostatic hyperplasia and gynecomastia in men and masculinization in women. These selective compounds bind to the androgen receptor inducing unique receptor conformations, which allow only certain co-activator and co-repressor proteins to interact. Unique receptor-cofactor ensembles confer differential regulation of target genes and other receptor-mediated pathways. This differential activity allows SARMs to have strong agonistic anabolic properties in target tissues such as muscle and bone, but function as antagonists or partial agonists in the prostate, uterus, and ovary. The discovery path resulting in the identification of GSK2881078A, GSK’s current SARM clinical asset, will be described. Structurally informed iterative design laid the foundation for the chemical series from which GSK078A emerged. GSK078A has been evaluated in a series of in vitro and in vivo assays exemplifying its activity as a SARM and clearly differentiating it from the androgenic sex hormones T and DHT.

Discovery of GSK2881078A: A selective androgen receptor modulator (SARM) for the treatment of muscle wasting disorders

249th National Meeting (2015)

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