Targeting the retinoid signaling pathway with YCT-529 for effective and reversible oral contraception in mice and primates

Introduction

Since nearly half of all pregnancies in the US and worldwide are unintended, a critical need exists for additional contraceptive options applicable throughout the reproductive lifespans of both women and men^{1, 2–3}. Women have multiple contraceptive options, but men are limited to condoms and vasectomy⁴. Testosterone and testosterone derivatives have been clinically evaluated for male contraception; however, none have been marketed⁵. The importance of dietary vitamin A and retinoid signaling for male germ cell development and differentiation has been recognized for many years⁶. All trans-retinoic acid (Fig. 1a) is an active metabolite of vitamin A that exerts its function, at least partly, by binding to retinoic acid receptors (RARs). The RARs α, β, and γ, are encoded by the Rara, Rarb, and Rarg genes in mice, and Rarα and Rarγ have been validated as contraceptive targets by genetic knockouts resulting in male sterility^7,8. Notably, the effects on spermatogenesis in the absence of RARα most resemble the loss of RAR signaling in vitamin A deficiency, and the mice are otherwise normal^7,8. Further, the effects on spermatogenesis in animals treated orally with the dual RARα/RARγ antagonist BMS-189453 (Fig. 1a, b) closely phenocopied the absence of RARα function. Importantly, the resulting male sterility is reversible^{9, 10–11}. We, therefore, wished to identify RARα−selective inhibitors for potential male non-hormonal contraception. Our study describes the development of YCT-529, a highly selective RARα antagonist that reduces sperm counts in mice and non-human primates. Mating studies with male mice treated with 10 mg/kg/day for 4 weeks show that YCT-529 is 99% effective in preventing pregnancies and that the mice fully regain fertility after drug cessation.

Fig. 1 [Images not available. See PDF.]

Chemical structures of retinoic acid and RAR antagonists, and in vitro ADMET data.

a Structures of agonist all-trans-retinoic acid, antagonists BMS-189453, BMS-189532, and YCT-529. The general ligand scaffold consists of a hydrophobic ring system (blue) and a conjugated acid or a benzoic acid (green) that are connected by a linker (pink). The linker group determines receptor subtype specificity. A large substituent on the hydrophobic ring (black) is required for antagonist activity. b IC₅₀ data for YCT-529, BMS-189453, and BMS-189532, and EC