Nav: Home

A step toward a birth control pill for men

March 13, 2016

SAN DIEGO, March 13, 2016 --Women can choose from a wide selection of birth control methods, including numerous oral contraceptives, but there's never been an analogous pill for men. That's not for lack of trying: For many years, scientists have attempted to formulate a male pill. Finally, a group of researchers has taken a step toward that goal by tweaking some experimental compounds that show promise.

The researchers present their work today at the 251st National Meeting & Exposition of the American Chemical Society (ACS). ACS, the world's largest scientific society, is holding the meeting here through Thursday. It features more than 12,500 presentations on a wide range of science topics.

One compound that's been studied as a potential male contraceptive is testosterone. "At certain doses it causes infertility," says Jillian Kyzer, a graduate student working on the topic. "But at those doses, it doesn't work for up to 20 percent of men, and it can cause side effects, including weight gain and a decrease in 'good' cholesterol."

Bringing any male contraceptive to market requires it to satisfy several requirements, explains Kyzer's team leader, Gunda I. Georg, Ph.D., who is based at the University of Minnesota College of Pharmacy. It would have to be soluble so it could be taken by mouth. It would start working fairly quickly, and it wouldn't diminish libido. It would be safe even if taken for decades. And because some users would eventually want to have children, its impact on fertility would be reversible, with no lingering ill effects on sperm or embryos. "That's a very high bar for bringing a male contraceptive to market," Georg points out.

These hurdles have driven many investigators from the hunt, yet Georg's team perseveres. "It would be wonderful to provide couples with a safe alternative because some women cannot take birth control pills," she says.

Drug companies, including Bristol-Myers Squibb (BMS), have created some experimental male contraceptives, but these too have drawbacks, Kyzer says. For instance, one of the company's test compounds is good at inhibiting fertility but isn't very soluble, so it can't be taken by mouth. "No one wants to inject themselves with a needle once a day or once a week for most of their lives," she notes.

Another Bristol-Myers Squibb experimental compound can be taken orally but isn't very selective in terms of its cellular targets in the body. That means the compound not only interacts with the retinoic acid receptor-α, which is involved in male fertility, but also with two other retinoic acid receptors that are unrelated to fertility. That flaw could cause side effects.

Kyzer and several of her colleagues are creating numerous substances that are similar in their chemical structure to the Bristol-Myers Squibb compounds. Although the optimal contraceptive for men remains elusive, Georg's team has made some progress. For example, the researchers are gaining a better understanding of how tweaks to the chemical structure of their test compounds affect the substances' cellular interactions in the body. One of those tweaks added a polar group to the molecule, which made the test compounds more soluble. Another tweak replaced an amide bond in the BMS compound with slightly different bonds that are known in the field of medicinal chemistry to mimic an amide bond. As intended, that change improved the test compounds' stability, meaning they would last longer in the body. Unfortunately, both types of modifications also reduced the specificity of the compounds for the intended retinoic acid receptor-α target.

The group continues to refine the chemical structures to achieve the ultimate balance of solubility, specificity and stability as they aim to design a better male pill. They are now investigating hybrid compounds that incorporate scaffolds and structural features from several other compounds known to interact with the retinoic acid receptor.
-end-
A press conference on this topic will be held Monday, March 14, at 10:30 a.m. Pacific time in the San Diego Convention Center. Reporters may check-in at Room 16B (Mezzanine) in person, or watch live on YouTube http://bit.ly/ACSliveSanDiego. To ask questions online, sign in with a Google account.

The researchers acknowledge funding from the Contraception Research Branch, Eunice Kennedy Shriver National Institute of Child Health & Human Development.

The American Chemical Society is a nonprofit organization chartered by the U.S. Congress. With more than 158,000 members, ACS is the world's largest scientific society and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.

To automatically receive news releases from the American Chemical Society, contact newsroom@acs.org.

Note to journalists: Please report that this research is being presented at a meeting of the American Chemical Society.

Follow us: Twitter | Facebook

Title

Design and Synthesis of Nuclear Receptor Antagonists Targeting RARα for Male Contraception

Abstract

The retinoic acid receptor-α (RARα) is a nuclear receptor that has been implicated in male contraception. In the absence of retinoic acid, RARα has been shown to prevent spermatogenesis by inhibiting DNA transcription.1 Previous work by Bristol Myers Squibb identified two RAR antagonists of interest: BMS 189453 and BMS 189532. While BMS 189453 has been shown to cause reversible infertility in mice when administered orally, it is non-selective over the β and γ isoforms; BMS 189532 is selective for RARα, but lacks oral bioavailability. The goal of this project is to design and synthesize selective, bioavailable antagonists of RARα based on the BMS scaffold, which can be broken down into three regions: a hydrophobic ring, a linker, and a carboxylic acid. The antagonists are tested using an iterative design process.

The first generation of compounds developed in our lab contained varying aryl substituents on the ring region and amide bioisosteres in the linker region. The compounds were evaluated using protein crystallography, isothermal titration calorimetry, and a luciferase reporter assay. Analysis of the RARα co-crystal structures determined that additional lipophilic substituents on the ring portion of the scaffold could increase selectivity. Alternative ring structures, including chromenes, are being pursued. Synthesis and evaluation of these compounds will be discussed.

Reference

1. Chung, S. S. W.; Cuellar, R. A. D.; Wang, X.; Reczek, P. R.; Georg, G. I.; Wolgemuth, D. J. ACS Med. Chem. Lett. 2013, 4, 446-450.

American Chemical Society

Related Fertility Articles:

Fertility preservation for children with differences of sex development
Article explores unique ethical issues for children with differences of sex development on whether or not they should pursue fertility preservation.
In roundworms, fats tip the scales of fertility
Two University of Colorado Boulder scientists have discovered how fat levels in a tiny soil-dwelling roundworm (C. elegans) can tip the balance between whether the worm makes eggs or sperm.
Fertility can hinge on swimming conditions in the uterus
A Washington State University researcher has found that the uterus in female mice contains enzymes that can break down semen, making it less gel-like, more watery, and therefore easier to swim in.
Ladies, this is why fertility declines with age
Researchers at the University of Montreal Hospital Research Center (CRCHUM) have discovered a possible new explanation for female infertility.
Many transgender individuals consider their fertility important, survey shows
Nearly one-fourth of transgender individuals in Toronto, Canada, regard their own fertility as important, but most lack knowledge regarding and access to reproductive options, a new survey finds.
A rapid, automated and inexpensive fertility test for men
Scientists have developed a low-cost and easy-to-use smartphone attachment that can quickly and accurately evaluate semen samples for at-home fertility testing, providing a potentially helpful resource for the more than 45 million couples worldwide who are affected by infertility.
Cows may offer clues to improving fertility in women
A Michigan State University researcher has received a $1.65 million grant that looks to bring a better understanding about fertility treatments in women by studying the effect of hormones on ovulation and reproduction in cows.
Men have a lot to learn about their own fertility
The first large-scale study of its kind has revealed that Canadian men generally lack knowledge about the risk factors contributing to male infertility.
Spinning semen provides a measurement of fertility
The maths of collective behavior has provided a new technique for selecting the best semen for artificial insemination in livestock.
Control of fertility: A new player identified
Individual small RNAs are responsible for controlling the expression of gonadoliberin or GnRH (Gonadotropin-Releasing Hormone), a neurohormone that controls sexual maturation, the appearance of puberty, and fertility in adults.

Related Fertility Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Bias And Perception
How does bias distort our thinking, our listening, our beliefs... and even our search results? How can we fight it? This hour, TED speakers explore ideas about the unconscious biases that shape us. Guests include writer and broadcaster Yassmin Abdel-Magied, climatologist J. Marshall Shepherd, journalist Andreas Ekström, and experimental psychologist Tony Salvador.
Now Playing: Science for the People

#513 Dinosaur Tails
This week: dinosaurs! We're discussing dinosaur tails, bipedalism, paleontology public outreach, dinosaur MOOCs, and other neat dinosaur related things with Dr. Scott Persons from the University of Alberta, who is also the author of the book "Dinosaurs of the Alberta Badlands".