SM-130686 (6-Carbamoyl-3-(2-chlorophenyl)-1-(2-diethylaminoethyl)-4-trifluoromethyloxindole
hydrochloride)

The Library (1995-1998)

Hidden in Plain Sight

How a Ghost Was Born in Osaka

In the mid-1990s, Sumitomo Pharmaceuticals in Osaka, Japan had accumulated a massive library of chemical compounds over decades of research. These were not custom-designed molecules — they were leftovers from previous drug development programs, forgotten experiments, and exploratory synthesis batches. This chemical graveyard held thousands of potential drug candidates, many of them never fully tested.

Meanwhile, scientists around the world were discovering ghrelin. In 1999, researchers found that ghrelin was the hormone that triggered the pituitary gland to release growth hormone. This was huge. If you could make a chemical that acted like ghrelin, you could boost growth hormone without injecting it. Companies began racing to design synthetic ghrelin-mimics.

The Sumitomo team took a different path. Instead of starting from scratch to design new molecules, they asked a simple question: what if the answer was already sitting in our library? They began screening thousands of existing compounds against the newly discovered ghrelin receptor (GHS-R). Most did nothing. But one oxindole compound stood out. Its structure was completely different from anything else being tested for this purpose.

The compound was called SM-130686. An oxindole is a carbon-ring structure found in some natural products and many synthetic drugs. SM-130686's ring had a chlorine atom attached to a benzene ring on one side, and a trifluoromethyl group (three fluorine atoms stuck together) on another side. These unusual chemical decorations gave the molecule special properties. When Sumitomo scientists tested SM-130686 in lab dishes with rat pituitary cells, it worked. It bound tightly to the GHS-R receptor and told the cells to release growth hormone.

What made SM-130686 special was not just that it worked, but that you could swallow it as a pill. Most other GH-releasing compounds had to be injected or dissolved under your tongue. An oral pill would be revolutionary. But this advantage came with a cost: SM-130686 was only a partial agonist. It activated the GHS-R receptor about 55% as hard as real ghrelin did. In other words, it turned the growth hormone faucet up to medium, never all the way.

No one knew yet if that would be enough.

The Proof (1999-2001)

Showing Its Muscle

SM-130686 Works in Living Rats

Once Sumitomo had SM-130686 in hand, the real testing began. In 1999 and 2000, Jun Nagamine and his team conducted animal studies in rats. They wanted to prove three things: Does it actually release growth hormone when you give it orally? Does it build muscle? And does it work safely without serious side effects?

The first test was simple but critical. They gave rats a single dose of SM-130686 by mouth (10 milligrams per kilogram of body weight). Then they measured growth hormone levels in the blood at different times. Within 20 to 45 minutes, growth hormone spiked dramatically. The hormone stayed elevated for over 60 minutes. The timing was perfect — fast enough to be useful, long enough to have real effects. This proved that SM-130686 could actually reach the bloodstream when swallowed, get to the pituitary gland, and trigger hormone release.

But a single spike is not the same as building muscle. So Nagamine's team ran a nine-day dosing study. They gave rats SM-130686 twice a day (10 mg/kg each time) for nine days straight. They measured body weight, body composition (how much is fat versus muscle), and various blood markers including IGF-I (insulin-like growth factor I, which is the hormone that actually tells your muscles to grow).

The results were striking. After nine days, the rats gained weight — 19.5 grams on average. But here is the crucial part: nearly all of that weight was lean muscle. The fat-free mass increased by 18.1 grams. In other words, the rats built muscle without getting fat. This is exactly what you want from a growth hormone drug. Regular weight gain with lots of fat is useless for medical treatment. But pure muscle gain means the drug is actually working at the biological level.

Blood tests showed that IGF-I levels were significantly higher six hours after the last dose. This is the chain of command: ghrelin → GHS-R activation → growth hormone release → IGF-I production → muscle growth. SM-130686 was lighting up the entire chain.

To prove it was really using the GHS-R receptor and not some other pathway, Nagamine did a clever experiment. He gave rats a drug that blocks the GHS-R receptor, then gave SM-130686. The growth hormone response disappeared. But when he gave rats a drug that blocks GHRH (a different hormone that also triggers GH release), SM-130686 still worked. This proved beyond doubt that SM-130686 works through the GHS-R, just like ghrelin does.

The compound was also safe. In the dosing studies, no serious side effects appeared. No organ damage. No toxicity. No unexpected reactions. The only thing that happened was controlled, predictable growth hormone release and muscle building.

The Publication (2001-2002)

Truth in Print

SM-130686 Enters Scientific Record

In 2001, Sumitomo published its findings. Jun Nagamine and colleagues submitted their animal study results to the Journal of Endocrinology, one of the most respected publications in hormone research. The paper, titled 'Pharmacological profile of a new orally active growth hormone secretagogue, SM-130686,' laid out all the evidence: potency data, GH release kinetics, muscle-building results, and safety information.

This was not a flashy discovery or a breakthrough that rocked the field. SM-130686 was just one more candidate in a growing crowd of GH-releasing compounds. But it had something most others did not: it was oral. You could swallow it as a pill.

That same year, Teruhisa Tokunaga published the medicinal chemistry paper in the Journal of Medicinal Chemistry. His paper was titled 'Oxindole Derivatives as Orally Active Potent Growth Hormone Secretagogues.' It described the entire chemical series, the optimization process, and why the oxindole scaffold worked so well for oral activity. Tokunaga explained the synthetic route — the step-by-step chemical reactions needed to build SM-130686 from raw materials. This information was crucial because it meant other chemists could now study the molecule, improve upon it, or develop related compounds.

The two papers together created a complete scientific record. Nagamine showed that SM-130686 worked biologically. Tokunaga showed how to make it chemically. Together, they positioned SM-130686 as a genuine pharmaceutical candidate.

But there was a problem no one could have predicted. SM-130686 was only a partial agonist — about 55% as strong as real ghrelin. This was great for safety and oral bioavailability, but it created a ceiling. No matter how much SM-130686 you gave to a rat or (theoretically) a human, you could never achieve the maximum growth hormone response that real ghrelin could produce. It was like a car that could only go 55 miles per hour on an empty road.

Meanwhile, other companies were developing full agonists — compounds that activated the GHS-R receptor 100% as hard as ghrelin did. Eli Lilly's MK-677 (ibutamoren) was moving through clinical trials. Other compounds were in the pipeline. In the race to develop an oral growth hormone secretagogue, Sumitomo had a solid runner, but not necessarily the fastest one.

The 2001 publication was both a triumph and a starting gun for a race that Sumitomo would not finish.

The Merger (2003-2006)

When Giants Collide

The Road Not Taken

In October 2005, Sumitomo Pharmaceuticals merged with Dainippon Pharmaceutical Company. This was a massive corporate event in Japan's pharmaceutical industry. But for SM-130686, it was a death knell.

When large companies merge, priorities shift. The new company — eventually called Dainippon Sumitomo Pharma — had to choose which research programs to keep and which to cut. Resources are finite. Management has to decide: What will make money? What fits our new corporate direction? What can we realistically take to market?

Dainippon Sumitomo Pharma decided to focus on psychiatry (mental health drugs), oncology (cancer drugs), and regenerative medicine. Growth hormone secretagogues did not fit this strategy. SM-130686 was shelved. There was no big announcement, no press release saying 'we are discontinuing SM-130686.' It simply stopped. Funding dried up. The research teams moved on to other projects. The compound that had shown such promise in rats — that built pure muscle, that worked orally, that had a clean safety profile — never went into human clinical trials.

No Phase 1 safety studies. No Phase 2 efficacy testing. No human patients ever tried SM-130686.

This was not unusual in pharma. Thousands of promising compounds get shelved every year. Companies have to make hard choices. The partial agonist profile may have played a role. If SM-130686 could only achieve 55% of maximum GH release, maybe it would not be strong enough to meet patients' medical needs. Maybe the development costs to prove safety and efficacy in humans would be too high for that level of benefit.

But there was also bad timing. The 2005 merger happened just as SM-130686 was positioned to move into human testing. A few more years, and it might have had a chance. A different corporate strategy, and the company might have prioritized GH drugs. History turned on small decisions.

Sumitomo's internal research continued in other areas. In 2006, Nagamine and colleagues published a review paper in the journal Combinatorial Chemistry & High Throughput Screening, summarizing the synthesis and pharmacology of SM-130686 — basically a retrospective look at what they had accomplished before discontinuation. It was like writing an obituary for a project while it was still technically alive.

But the compound did not disappear completely. Academic researchers kept studying it. In 2009, Motomu Kanai at the University of Tokyo published a paper showing how to synthesize SM-130686 enantioselectively — meaning how to make only the active S-form, not the inactive R-form. This showed that scientific curiosity about the molecule had not died. Even though Sumitomo had abandoned it commercially, the academic world still saw potential.

SM-130686 had become a ghost — technically alive in the scientific literature and in chemical supplier catalogs, but never to be tested in a human patient.

The Ghost (2006-Present)

Living in Scientific Limbo

What Could Have Been

After 2006, SM-130686 entered a strange limbo. It was not a failure — all the data showed it worked. It was not forgotten — researchers kept publishing about it. But it was no longer being developed for medical use. It was abandoned, but not dead.

One unexpected way SM-130686 entered the public consciousness was through anti-doping agencies. In 2006, researchers published detection methods for finding SM-130686 in urine. The World Anti-Doping Agency (WADA) became interested in the molecule, even though it had never been approved for human use. Why? Because athletes in strength sports might try to use it to gain a competitive edge. Growth hormone increases muscle mass, strength, and recovery speed — all valuable for athletic performance.

The fact that WADA developed detection tests for SM-130686 is ironic. The compound was so obscure that it never reached patients, yet it was significant enough to worry anti-doping authorities. This suggests that even in its shelved state, SM-130686 represented a potential threat to fair competition.

Meanwhile, SM-130686 continued to exist as a research chemical. Major chemical suppliers like Sigma-Aldrich, Toronto Research Chemicals (TRC), and other firms that sell compounds for laboratory use began offering SM-130686 to researchers worldwide. If you have a research license and the money, you can still buy SM-130686 today. Researchers studying GHS-R biology, testing new GH-releasing approaches, or comparing different agonist profiles might purchase SM-130686 for their experiments.

Academic interest persisted. In 2009, Motomu Kanai's paper on enantioselective synthesis was published. This work was not just academic curiosity — it showed that if someone wanted to develop SM-130686 further, they now had a better way to manufacture it. Only the active S-enantiomer would be made, eliminating waste of the inactive R-form.

Over the past 15 years, SM-130686 has appeared in dozens of scientific papers — mostly in comparisons with other GHS-R agonists, mechanistic studies of the GHS-R receptor itself, or doping-related research. But it has never advanced closer to a human patient. The compound sits frozen in time at 2005, when it was suspended from development.

Compare SM-130686's fate to MK-677 (ibutamoren), which was being developed around the same time. MK-677 is now in Phase 3 trials and approved in some countries. Or to other GHS-R agonists that have since reached the clinic. SM-130686 represents the brilliant road not taken — a compound with genuine promise that fell victim to corporate timing and changing priorities.

Today, SM-130686 serves mainly as a research tool. It is used to study how the GHS-R receptor works, to test new signaling pathways, to compare against newer agonists. It is valuable to science, but not to patients. The ghost of the chemical library has found a quiet place in the academic world, forever brilliant and forever untested in humans.