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The long-awaited male contraceptive pill has a new candidate. Presented at the American Chemical Society (ACS) meeting, this non-hormonal male contraceptive has been shown to effectively prevent pregnancy in mice, with no obvious side effects.
Until now, women have many options for birth control, from pills to patches to intrauterine devices, and partly as a result, they bear most of the burden of preventing pregnancy.
Currently, men only have two effective options for birth control: condoms masculine and the vasectomy. However, condoms are single-use and prone to failure.
In contrast, vasectomy, a surgical procedure, is considered a permanent form of male sterilization.
And while they can sometimes be reversed, reversal surgery is expensive and not always successful.
Therefore, men need an effective, long-lasting but reversible contraceptive, similar to the contraceptive pill for women.
“Scientists have tried for decades to develop an effective male oral contraceptive, but there are still no approved drugs on the market,” says Abdullah Al Noman, a researcher at the University of Minnesota (USA) and author of the work.
Most of the compounds currently in clinical trials target the male sex hormone testosterone, which could lead to side effects such as weight gain, depression, and increased low-density lipoprotein (LDL) cholesterol levels. “We wanted to develop a non-hormonal male contraceptive to avoid these side effects,” explains Noman.
To develop their non-hormonal male contraceptive, the researchers targeted a retinoic acid receptor alpha (RAR-α) protein. This protein belongs to a family of three nuclear receptors that bind retinoic acid, a form of vitamin A that plays important roles in cell growth, differentiation (including sperm formation), and embryonic development. Deletion of the RAR-α gene in male mice renders them sterile, with no obvious side effects.
Other scientists have developed an oral compound that inhibits all three members of the RAR family (RAR-α, -β, and -γ) and causes reversible infertility in male mice, but this team wanted to find a drug that was specific for RAR-α and , therefore, with fewer likely side effects.
The researchers examined the crystal structures of RAR-α, -β, and -γ bound to retinoic acid, identifying structural differences in the ways the three receptors bind their common ligand. Armed with this information, they designed and synthesized approximately 100 compounds and tested their ability to selectively inhibit RAR-α in cells. They identified a compound, called YCT529, that inhibited RAR-α nearly 500 times more potently than RAR-β and -γ.
When administered orally to male mice for 4 weeks, YCT529 dramatically reduced sperm count and was 99% effective in preventing pregnancy, with no observable side effects. The mice were able to father pups again 4 to 6 weeks after stopping the compound.
According to the scientists, YCT529 will begin testing in human clinical trials in the third or fourth quarter of 2022.
“Because it can be difficult to predict whether a compound that looks good in animal studies will also work in human trials, we are currently exploring other compounds,” they say.
To identify these next-generation compounds, the researchers are modifying the existing compound and testing new structural scaffolds. They hope that their efforts will finally come true the elusive male oral contraceptive.
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