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

Abstract

The retinoic acid receptor alpha (Rarα) has been validated as a male contraceptive target by genetic knockouts resulting in male sterility. The effects on spermatogenesis in the absence of RARα resemble the loss of RAR signaling in vitamin A deficiency, and the mice are otherwise normal. The effects on spermatogenesis in animals treated orally with the dual RARα/RARγ antagonist BMS-189453 closely phenocopies the absence of RARα function. Notably, the resulting male sterility is reversible. We, therefore, wished to identify RARα−selective inhibitors for potential male non-hormonal contraception. YCT-529 was investigated for RARα selective inhibition, physicochemical characteristics, oral bioavailability, and pharmacokinetic properties in mice and non-human primates. It was assessed in mouse mating trials to determine the most effective dosing regimen to induce infertility in male mice and in male non-human primates to reduce sperm levels. Characterization of YCT-529 shows suitable biochemical, physicochemical, and pharmacokinetic properties for in vivo testing. YCT-529 inhibits mouse fertility of male mice within 4 weeks of oral administration, correlating with disrupted spermatogenesis demonstrating specific inhibition of the RARα pathway. Within 6 weeks after cessation of dosing, mouse fertility reverses. Furthermore, YCT-529 inhibits sperm production in a non-human primate model within 2 weeks of oral dosing without adverse side effects. Within 10–15 weeks after cessation of dosing, non-human primates’ sperm counts fully reverses. These results lay the groundwork for evaluating YCT-529 in human clinical trials. There is currently no oral birth control option available to men to prevent pregnancy in their sexual partners. YCT-529 is a non-hormonal male contraceptive that could be a potential drug for men to take to prevent pregnancy. YCT-529 works by interfering with vitamin A signaling necessary for sperm production and fertility. Our study examined its effectiveness and side effects in mice and non-human primates. We show that this oral drug causes infertility in mice, which can be reversed after stopping its consumption. In male non-human primates, sperm production is inhibited (this is how the drug prevents pregnancy) within 2 weeks of starting YCT-529 without adverse side effects and the animals regain fertility after stopping treatment. Mannowetz and Chung et al. investigated the properties and efficacy of the RARα selective antagonist YCT-529 as a male contraceptive. Mouse and non-human primates experienced fertility inhibition through disruption of spermatogenesis which was reversed upon cessation of oral administration.

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