Development of a Second-Generation RARα Selective Antagonist as an Orally Bioavailable, Effective, Safe, and Reversible Male Contraceptive.

We report the design and SAR studies of benzopyran-, benzofuran-, and benzothiophene-derived inhibitors of the retinoic acid receptor alpha (RARα) for male contraception. SAR studies identified critical features influencing activity, such as the optimal positioning of antagonism moieties and substituents, leading to the discovery of (S)-4-(5-(2,8-dimethyl-5-(p-tolyl)-2H-chromen-3-yl)-1H-pyrrol-2-yl)benzoic acid (compound 23). Compound 23 is a highly potent RARα inhibitor (IC50 = 0.051 nM) with excellent selectivity (>1650-fold over RARβ and >1960-fold over RARγ) and ADMET properties. Compound 23 is orally bioavailable and reduces sperm counts in mice for a full male contraceptive effect with a minimum effective dose between 0.3 and 1 mg/kg/day, with complete recovery after drug continuation. Using imaging mass spectrometry, we analyzed the spatial distribution of compound 23 in mouse seminiferous tubules. Compound 23 does not cross the blood-testis barrier and therefore must exert its activity during the initial phases of spermatogenesis.