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Optimizing ligand efficiency of selective androgen receptor modulators (SARMs)
Handlon, A. L., Schaller, L. T., Leesnitzer, L. M., Merrihew, R. V., Poole, C., Ulrich, J. C., Wilson, J. W., Cadilla, R., & Turnbull, P. (2016). Optimizing ligand efficiency of selective androgen receptor modulators (SARMs). ACS Medicinal Chemistry Letters, 7(1), 83-88. https://doi.org/10.1021/acsmedchemlett.5b00377
A series of selective androgen receptor modulators (SARMs) containing the 1-(trifluoromethyl)benzyl alcohol core have been optimized for androgen receptor (AR) potency and drug-like properties. We have taken advantage of the lipophilic ligand efficiency (LLE) parameter as a guide to interpret the effect of structural changes on AR activity. Over the course of optimization efforts the LLE increased over 3 log units leading to a SARM 43 with nanomolar potency, good aqueous kinetic solubility (>700 mu M), and high oral bioavailability in rats (83%).