Development of selective RARα antagonists as male contraceptive agents

The quest for an effective male contraceptive agent has begun decades ago with no approved pills to date. Compounds undergoing clinical trials are all targeted on male sex hormone testosterone which could lead to hormonal side effects such as weight gain, depression, increased low-density lipoproteins, etc. Our effort focused on developing a non-hormonal male contraceptive to avoid the hormonal side effects. Vitamin A has long been known to be essential for male fertility and vitamin-A-deficient diet causes mammalian male sterility. One particular receptor of vitamin A metabolite retinoic acid (RARα) is validated as the target for male contraception by gene knockout studies. Also, oral administration pan-RAR antagonist BMS-189453 which inhibits the activity of RAR α, β, and γ lead to reversible sterility in male mice. Knocking out RAR alpha and treatment with a pan-RAR antagonist did not present any significant side effects in mice. We pursued to develop a selective RARα antagonist as a safe, effective, and reversible male contraceptive agent with no off-target effects on RARβ and RARγ. Based on the published crystal structures of RARα-ligand complex as well as structures elucidated by us, we envisioned to exploit the structural differences between RARα, β, and γ ligand-binding domain to achieve RARα selectivity. Also, the structural differences between RARα bound to the agonist and the antagonist facilitated the design of full antagonists. Aided by all the structural information, we designed and synthesized about 100 compounds and evaluated RARα antagonist activity and selectivity using a luciferase-reporter cell assay. We obtained several antagonists with single-digit nanomolar IC₅₀ values for RARα with excellent selectivity over RARβ and RARγ. One RARα-selective antagonist showed good oral bioavailability and desired pharmacokinetic properties in mice, and upon oral administration, it showed complete inhibition of embryo formation in mating studies. Modification of active compounds is ongoing to obtain additional potent and selective inhibitors with good pharmacodynamic and pharmacokinetic properties.