Retinoic acid receptor alpha (RARA), a nuclear receptor protein, has been validated as a target for male contraception by gene knockout studies and also pharmacologically using a pan-retinoic acid receptor antagonist. Retinoic acid receptor alpha activity is indispensable for the spermatogenic process, and therefore its antagonists have potential as male contraceptive agents. This review discusses the effects of systematic dosing regimen modifications of the orally bioavailable and reversible pan-antagonist BMS-189453 as well as studies with the alpha-selective antagonists BMS-189532 and BMS-189614 in a murine model. We also provide an overview of structure-activity studies of retinoic acid receptor alpha antagonists that provide insight for the design of novel alpha-selective ligands.
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*Correspondence: Department of Medicinal Chemistry, College of Pharmacy, Institute for Therapeutics Discovery and Development, University of Minnesota, 717 Delaware Street, SE, Minneapolis, MN 55414, USA. Tel: (612) 626-6320; E-mail: firstname.lastname@example.org †Grant Support: This work was supported by National Institute of Child Health and Human Development Grants U01-HD060479 and U54-HD093540/P50-HD093540, project 1 (to D.J.W. and S.S.W.C.) and HHSN275201300017C (to G.I.G) and U54-HD093540/P50-HD093540 (to G.I.G.).
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- Male contraception
- Mouse model
- Retinoic acid receptor
- Structure-activity relationships