Nearly two decades before the approval of a daily oral GLP-1 pill for weight management, UC Riverside bioengineering professor Jiayu Liao contributed to research demonstrating that a nonpeptide molecule could activate the GLP-1 receptor and produce biological effects in animals.
That early work is part of the scientific history surrounding a new generation of oral GLP-1 drugs.
On April 1, 2026, the U.S. Food and Drug Administration approved Foundayo, the brand name for orforglipron, for chronic weight management in adults with obesity or certain adults with overweight and a weight-related health condition. The agency approved the drug 50 days after its application was filed, a record in the past two decades, making it the first approved drug through the FDA Commissioner’s National Priority Voucher pilot program.
Foundayo is a once-daily, oral, small-molecule GLP-1 receptor agonist for obesity treatment. Unlike peptide-based GLP-1 medicines, the drug does not need to be injected. Its indication for diabetes treatment is still under review by the FDA.
Glucagon-like peptide-1, or GLP-1, is a hormone involved in regulating blood sugar, food intake, and appetite. Drugs that activate the GLP-1 receptor have become important treatments for diabetes and obesity. GLP-1 and related peptides have also become a major focus in the development of diabetes and obesity drugs in recent decades. For years, however, developing smaller, nonpeptide molecules capable of effectively activating the receptor presented a significant drug-discovery challenge.
Liao and collaborators were pursuing that problem by the mid-2000s.
In a 2007 paper published in the Proceedings of the National Academy of Sciences, the researchers reported the discovery and testing of Boc5, a nonpeptide molecule that activated the GLP-1 receptor. Liao initiated the idea and helped design the research and analyze the data. The research was conducted through the National Center for Drug Screening in Shanghai, and the paper listed Liao’s present address as UC Riverside’s Department of Bioengineering.
The researchers began by screening a library of 48,160 synthetic and natural compounds. Their work ultimately led them to Boc5, which was a dimer of the original molecule. Boc5 produced GLP-1 receptor activity in laboratory experiments and demonstrated effects in mouse models of diabetes and obesity.
In the animal studies, Boc5 reduced food intake and improved measures of blood sugar regulation. After six weeks of treatment, researchers reported improved glucose tolerance and reductions in HbA1c, a measure of average blood sugar, in diabetic mice. The experiments also found less weight gain among Boc5-treated mice than untreated diabetic mice.
“What we aimed to do at that time was discover small molecules that could activate the GLP-1 receptor as a scientific breakthrough,” Liao said. “We hoped this could lead to a completely new drug modality that would be more convenient for patients and less costly while preserving similar efficacy.”
The findings provided the first evidence that a nonpeptide compound could activate the GLP-1 receptor and have measurable effects in a living animal, extending earlier work that had largely demonstrated small-molecule activity in laboratory systems. The discovery challenged the prevailing industry view that a small molecule could not activate the GLP-1 receptor.
Liao continued investigating nonpeptide approaches to the receptor. He and collaborators later developed phenylalanine derivatives designed to modulate GLP-1 receptor activity. These compounds were orally available and demonstrated efficacy in animal models of both diabetes and obesity. Their work resulted in a U.S. patent for “Phenylalanine derivatives and their use as non-peptide GLP-1 receptor modulators”, which was granted in 2014. According to Liao, it was the world’s first issued patent for a small-molecule agonist of the GLP-1 receptor.
Years later, both strands of that earlier research appeared in the scientific literature describing a compound that would eventually become orforglipron.
In 2020, researchers published a PNAS paper describing LY3502970, now known as orforglipron. The researchers described it as a potent, selective small-molecule GLP-1 receptor agonist with properties compatible with oral dosing in humans. The paper cited both the earlier Boc5 study and the phenylalanine-derivative patent involving Liao as part of previous research into nonpeptide GLP-1 receptor compounds.
Boc5 did not become orforglipron, and the drugs emerged from separate research and development efforts. According to Eli Lilly and Company, orforglipron was discovered by Chugai Pharmaceutical Co. and licensed to Lilly in 2018. Lilly subsequently led its clinical development. Liao said, however, that the original concept behind orforglipron and its pharmacophore can be traced to Boc5.
The connection lies in the scientific challenge researchers pursued over many years: whether a receptor successfully targeted by peptide medicines could also be activated with smaller, nonpeptide molecules suitable for development as oral drugs.
“Dr. Liao helped disprove the industry consensus that a small molecule couldn't activate the GLP-1 receptor,” said Yong Zhu of Lily Asian Fund. “That work seeded the chemistry lineage behind Lilly's orforglipron, or Foundayo, the first approved oral small-molecule GLP-1RA, and many of the 60-plus programs now in development.”
The FDA approval brings that long-running research effort into a new phase. It also offers a reminder that advances reaching patients today can trace part of their scientific history to experiments conducted years, and sometimes decades, earlier.