The Story Behind the First Nonsteroidal Androgen Receptor Modulators

The development of selective androgen receptor modulators (SARMs) marked a turning point in hormone therapy and anabolic research. In the late 20th century, scientists achieved initial scientific breakthroughs that led to the first nonsteroidal SARMs – compounds that promised muscle and bone benefits without the side effects of steroids. The story of these pioneering molecules is intertwined with historical steroid use, pharmaceutical innovation, and some visionary scientific pioneers. This article explores the historical context of anabolic agents, the emergence of the SARM concept in the 1990s, and how early SARMs like Andarine and Ostarine were discovered, setting the stage for a new era in pharmacology.

Historical Limitations of Anabolic Steroids and the Need for Selectivity

Throughout the mid-20th century, anabolic steroids like testosterone and its derivatives were the primary means to enhance muscle growth or treat wasting diseases. However, traditional steroids had inherent limitations. These hormones activated the androgen receptor throughout the body without discrimination, leading to a mix of desired anabolic effects and undesirable side effects. For example, testosterone therapy could stimulate muscle and bone growth, but it also enlarged the prostate, caused acne and hair loss, and in women could induce masculinizing changes. Chemists tried modifying testosterone’s structure (creating drugs like nandrolone in the 1950s) to reduce side effects. Nandrolone was a steroid alternative that indeed caused slightly less prostate stimulation and other androgenic issues than testosterone. Yet even such improved anabolic steroids could not fully separate muscle-building benefits from androgenic side effects. This lack of tissue selectivity meant patients and athletes using steroids invariably faced health risks like hormonal imbalances, liver strain, or virilization.

By the 1980s, the medical community recognized that a safer solution was needed. A key insight came from another field of hormone therapy: selective estrogen receptor modulators (SERMs). Drugs like tamoxifen showed it was possible to tweak a hormone receptor’s activity in a tissue-selective way – tamoxifen could block estrogen’s effects in breast tissue (treating cancer) while still acting somewhat like estrogen in bone tissue (helping density). This concept of selective modulation inspired researchers to ask if the same could be done for the androgen receptor. Additionally, earlier anti-androgen drugs provided a clue: nonsteroidal molecules like flutamide (introduced in the 1970s to treat prostate cancer) could bind the androgen receptor and block it. If a nonsteroidal chemical could bind the receptor as an antagonist, could chemists design one that acts as an agonist (activator) in muscle? These ideas set the stage for a new research frontier. The goal was to create steroid alternatives that build muscle and bone without the steroid baggage – in short, to achieve the anabolic benefits without the drawbacks.

The Emergence of SARMs in the 1990s: Initial Scientific Breakthroughs

The 1990s SARMs research efforts transformed those early ideas into reality. It was during this decade that the term “Selective Androgen Receptor Modulator” was coined and the first nonsteroidal SARMs were discovered. The initial scientific breakthroughs came in the late 1990s from a handful of pioneering scientists. In 1998, Dr. James T. Dalton, a pharmaceutical scientist, and his team reported a landmark discovery: they had identified a nonsteroidal molecule that activated the androgen receptor’s muscle-building pathway. This compound, essentially the first nonsteroidal SARM, was a modified analog of an anti-androgen that behaved like an anabolic agent. Dalton’s 1998 publication proved that a small synthetic molecule unrelated to testosterone could mimic the hormone’s effects on target tissues. It was a groundbreaking research milestone – for the first time, researchers saw anabolic activity (in cell and animal models) without a steroid structure.

Around the same time, the concept was formalized by Dr. Enrique (Henry) Negro-Vilar, an endocrinologist and research director who became one of the term’s early champions. In 1999, Negro-Vilar authored a visionary review article proclaiming selective androgen receptor modulators as a “novel approach to androgen therapy for the new millennium.” He defined SARMs as tissue-selective AR ligands that could be orally active and target muscle and bone while sparing other tissues. This helped solidify the SARM concept in the scientific community. The historical context here is important: by the end of the ’90s, scientists had decades of androgen receptor research behind them, plus tools like receptor assays and animal models to test selectivity. With proof from Dalton’s work that nonsteroidal agonists were possible, and Negro-Vilar’s enthusiastic promotion of the idea, a wave of pharmaceutical innovation was about to begin.

Importantly, multiple groups converged on the problem at once. Dalton’s discovery was one part of the puzzle; elsewhere, companies like Ligand Pharmaceuticals were also exploring nonsteroidal AR ligands. In the late 90s, Ligand developed a series of drug candidates in completely different chemical families (for example, quinolinone structures) that also activated the AR. Thus, by 1998–1999, the first nonsteroidal SARMs from different laboratories were demonstrating that tissue-selective androgen receptor modulation could be achieved. The stage was set for rapid SARMs development heading into the 2000s.

Scientific Pioneers and Early SARM Compounds (Andarine and Ostarine)

With the proof-of-concept established, there was a burst of progress in the early 2000s. A few key figures drove much of this initial progress. Dr. James Dalton continued his work by co-founding a biotech company (GTx Inc.) dedicated to SARMs, while others like Dr. Negro-Vilar (at Ligand) guided corporate research programs. Together, academic labs and industry teams raced to create optimized SARM molecules. Early SARMs compounds generally fell into two chemical families: aryl propionamides and quinolines/quinolinones. The aryl propionamides were inspired by nonsteroidal antiandrogens (like bicalutamide); chemists tweaked those structures to turn receptor blockers into receptor activators. One of the very first SARM candidates, known as S-1, came from this approach in the late ’90s – it was an analog that in lab tests acted like an androgen. Building on S-1, Dalton’s GTx group developed a series of compounds, among which Andarine (code named S-4) became noteworthy. Andarine (also called GTx-007) was among the first nonsteroidal SARMs to show clear anabolic effects in live animals. In a classic rat study (the Hershberger assay), an Andarine-like compound was shown to increase the weight of the levator ani muscle (a muscle responsiveness test) while causing much less prostate enlargement than testosterone. This was a landmark proof that tissue selectivity was not just theoretical – a groundbreaking discovery in pharmacology demonstrating muscle could be built with minimal impact on other organs.

Parallel to the aryl propionamides, Ligand Pharmaceuticals and other teams explored polycyclic structures. They introduced compounds like LGD-3303 and later LGD-4033 (ligandrol) in the early 2000s, showing that different chemical scaffolds could also hit the AR selectively. But perhaps the most famous early SARM to emerge was Ostarine. Ostarine (also known as enobosarm or GTx-024) is an aryl propionamide SARM that Dalton’s team developed after Andarine. It incorporated further chemical refinements to improve oral activity and selectivity. By the mid-2000s, Ostarine had become the flagship SARM in clinical development – in fact, it was the first nonsteroidal SARM to enter human trials. Ostarine demonstrated increases in lean muscle mass in Phase II studies without significant side effects on the prostate or hair, validating the approach in humans. While 1990s SARMs research had been about discovery and animal tests, the 2000s saw these early SARM compounds progress to real clinical testing.

Andarine and Ostarine highlight the promise and evolution of early SARMs. Andarine, as a first-generation SARM, was potent in animal models and proved that an orally administered, nonsteroidal molecule could act like an anabolic steroid in muscle tissue. It also taught researchers about the nuances of SARM chemistry – for example, Andarine’s particular structure (with a nitro group on its ring) was later associated with some idiosyncratic effects like mild visual disturbance in users, prompting chemists to adjust future designs. Ostarine, coming a few years later, benefited from those lessons. It featured a refined structure (a cyano group instead of Andarine’s nitro group) and excellent pharmacokinetic properties, making it suitable for human use. Together, these compounds were early scientific breakthroughs that proved selective androgen receptor activation could be harnessed as a therapy. By demonstrating significant muscle and bone strengthening effects with fewer side effects, the first nonsteroidal SARMs like Andarine and Ostarine created a blueprint for subsequent drug development.

Legacy and Impact in Pharmacology

The advent of the first nonsteroidal SARMs has left a lasting legacy in pharmacology. These pioneering compounds ushered in a new era of drug design for hormone receptors. For one, they expanded the notion that we can separate an anabolic effect from an androgenic effect – an idea that was once deemed nearly impossible with one hormone receptor. This success has encouraged researchers to pursue selective modulators for other steroid hormone receptors beyond just estrogen and androgen, applying similar principles of tissue targeting. In the pharmaceutical industry, the 2000s and 2010s saw major companies and startups alike invest in SARM research. Companies such as Eli Lilly, GlaxoSmithKline, and Pfizer jumped in early, patenting novel SARM scaffolds and testing various candidates for conditions like muscle wasting, osteoporosis, and even benign prostate enlargement. The concept of tissue selectivity became a core strategy in designing safer anabolic therapies.

From a therapeutic standpoint, the initial SARMs like Ostarine showed real-world potential – for example, helping elderly patients gain muscle or cancer patients counteract cachexia (extreme weight loss). Although as of the mid-2020s no SARM has yet obtained full regulatory approval as a prescription drug, the research continues and has advanced our understanding of androgen biology. The first SARMs taught scientists about the androgen receptor’s structure and how different ligands can induce different receptor shapes and gene activation patterns (somewhat like a “dimmer switch” effect). Such pharmacological advancements inform ongoing drug discovery efforts not just for SARMs but across endocrine pharmacology.

There is also a broader societal impact. The emergence of SARMs quickly caught the attention of the fitness and sports world. By the late 2000s, some of these compounds had leaked into the black market as performance enhancers, touted as “legal steroids” due to their muscle-building efficacy and oral form. Sports authorities reacted by adding SARMs to banned substance lists (the World Anti-Doping Agency banned them in 2008), underscoring that the first nonsteroidal SARMs were potent enough to be considered doping agents. This side story highlights that groundbreaking medical discoveries can have unintended off-label popularity. Nonetheless, the primary legacy remains scientific and medical: those initial scientific breakthroughs in the 1990s fundamentally changed how researchers approach the design of hormone-based therapies. The first nonsteroidal SARMs proved it was possible to have the anabolic cake and not eat the side-effect cake, so to speak. They opened a new paradigm where drugs could be designed to fine-tune the androgen receptor, offering targeted anabolic therapy for patients in need, from osteoporosis to muscle dystrophy. Future generations of SARMs and related drugs will always trace their lineage back to those first discoveries and the scientists who dared to rethink androgen therapy.

Conclusion

The story of the first nonsteroidal SARMs is a testament to innovation born from necessity. Faced with the blunt instrument of anabolic steroids, scientists sought a smarter solution and delivered one of the late 20th century’s major pharmaceutical innovations. By harnessing receptor biology and creative chemistry, early pioneers like Dalton and Negro-Vilar unlocked a new class of medication that continues to inspire research today. These selective androgen receptor modulators began as a bold idea in the 1990s and evolved into a rich field of study, bridging the gap between powerful hormonal effects and patient safety. The journey from steroid hormones to first nonsteroidal SARMs underscores how groundbreaking research and persistence can change the landscape of therapy. As we move forward, the legacy of those first SARMs lives on in ongoing clinical trials, emerging drug candidates, and the hope that truly selective anabolic treatments will one day become mainstream medicine.

FAQ

Who discovered the first nonsteroidal SARMs?
The first nonsteroidal SARMs were discovered by Dr. James T. Dalton and his research team in 1998. Dalton’s group was the first to identify a nonsteroidal compound that could activate the androgen receptor to produce anabolic effects, essentially marking the inception of SARMs.

Why were nonsteroidal SARMs a groundbreaking discovery?
They were groundbreaking because they proved that it’s possible to selectively stimulate muscle and bone growth without using a steroid structure. Prior to this, anabolic effects were almost exclusively achieved with traditional steroids and their broad side effects. The discovery of nonsteroidal SARMs showed a new way forward – drugs could be designed to target the androgen receptor in a controlled, tissue-selective manner. This opened up an entirely new paradigm in drug development for hormone-related conditions, offering the potential of steroid-like benefits with far fewer side effects.

What were the earliest nonsteroidal SARMs developed?
The earliest nonsteroidal SARMs emerged in the late 1990s and early 2000s. The very first prototype was the compound reported by Dalton’s team in 1998 (often referred to simply as the first SARM discovery). Shortly after, Andarine (known as S-4) was developed as an early SARM that showed anabolic activity in animal tests. Another pivotal early SARM was Ostarine (GTx-024, or enobosarm), which was developed in the early 2000s and became the first SARM tested extensively in humans. These compounds – along with others like early research compounds from Ligand Pharmaceuticals (e.g., LGD-series SARMs) – were among the first generation of SARMs that demonstrated the feasibility of selective androgen receptor modulation.