Developing anti-obesity medications (AOM) is challenging for both technical and social reasons. This article introduces the history and progress of anti-obesity Medications (AOMs).

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Anti-obesity Medications (AOMs): History And
Progress
According to statistics from the World Health Organization (WHO), nearly 2 billion people
are overweight or obese worldwide. From 1975 to 2016, the global obesity rate has nearly
tripled. Every year, overweight or obesity causes 2.8 million deaths. Obese people not
only have inconvenience and decreased exercise capacity, but also have an increased
risk of developing type 2 diabetes (T2D) and cardiovascular disease (CVD), as well as
death from cancers of the esophagus, colorectal, liver, gallbladder, pancreas and
kidney. It is estimated that 4-9% of cancer diagnoses are due to excess body fat, and
obesity is associated with a poorer prognosis for a variety of malignant diseases.
Figure 1. Obesity-related metabolic diseases
Recently, a review paper entitled: Anti-obesity drug discovery: advances and
challenges was published on Nature Reviews Drug Discovery, which comprehensively
introduced the development process of anti-obesity drugs and the latest developments
and challenges faced.

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More and more people realize that obesity is a chronic degenerative disease. Due to the
limited efficacy of lifestyle and behavior interventions, it is necessary to upgrade obesity
treatment strategies by adding drugs and/or surgical interventions. Bariatric surgery is the
most effective way to lose weight. Nevertheless, surgical intervention cannot meet the
extent of global medical needs.
Developing anti-obesity medications (AOM) is challenging for both technical and social
reasons. In the past, there have been a series of AOM-induced problems after regulatory
approval. Most of these are associated with adverse cardiovascular reactions
(Sibutramine, Fenfluramine, Dexfenfluramine, Rainbow pills), increased risk of suicide
(rimonabant), or increased drug dependence and abuse (methamphetamine).
Until recently, the latest clinical trials of GLP1R agonist drugs are making people believe
that breakthrough drug-based obesity treatments can be achieved.
On June 4, 2021, the U.S. FDA approved Novo Nordisk's semaglutide as an anti-obesity
drug under the trade name wegovy. Semaglutide has an outstanding weight-loss
effect. It is the first time that a drug has been used to achieve weight loss that was
previously only possible with surgery.
Figure 2. Wegovy

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The drug was originally used to treat diabetes. It is a structural analogue of human
glucagon-like peptide 1 (GLP-1), which can mimic its effect, reduce hunger, reduce diet,
and reduce calorie intake. Therefore, the effect is outstanding in terms of weight loss.
Phase 3 clinical trial results showed that participants lost an average of 15.3 kg.
Previously, another GLP1R agonist, liraglutide, was approved by the FDA for the
treatment of adult obesity in 2014.
The history of anti-obesity medications
The anti-obesity medications has a long and tortuous history. In the last century, drug
treatments for obesity included amphetamine, thyroid hormone, dinitrophenol, and various
drug combinations. Due to serious side effects, these drugs were revoked shortly after
regulatory approval.
The early development of AOMs has some obvious problems, but the recently approved
obesity drugs have improved a lot. Orlistat, naltrexone/bupropion, liraglutide and
Semalutide have all been approved. Bupropion is a reuptake inhibitor of dopamine and
norepinephrine. Although the opioid receptor antagonist naltrexone does not cause weight
loss in monotherapy, it reduces food intake when used in combination with Bupropion.
In 2014, Liraglutide 3mg became the first GLP1-based AOM to enter the market.
Semalutide 2.4mg, recently approved by the FDA, reduced average body weight by about
15% after 68 weeks of treatment (compared to about 2.4% in the placebo
group). Although there are typical GLP1-related adverse reactions, the drug is generally
well tolerated.

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Figure 3. History of weight loss drugs

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Novel anti-obesity therapies
At present, some emerging therapeutic targets have attracted the attention of the scientific
community. These novel drug candidates represent the latest advances in human obesity
treatment research.
Figure 4. Weight loss drugs in clinical development
GLP-1 related drugs

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The mechanism of action of GLP-1 agonists for weight loss is multi-factorial, and the
improvement of intestinal, brain and systemic insulin sensitivity all contribute to the
efficacy.
Figure 5. GLP-1
At the end of 2014, liraglutide 3mg became the first GLP1R agonist approved for the
treatment of obesity, which is approximately twice the highest dose used in T2D therapy.
After 1 year of treatment, subjects taking liraglutide lost an average of 8% in weight, while
the control group lost an average of 2.6% in weight. Weight loss is related to
improvements in insulin sensitivity, circulating lipids, and blood pressure. These results
confirm that GLP1R agonists can be used to improve the metabolism of obese patients,
reduce weight moderately, and reduce cardiovascular disease risk at the same time.
Semaglutide was approved in June 2021 for the treatment of obese or overweight
adults. In a 1-year phase II study, the daily dose was about 10% of the high-dose
liraglutide, and the weight loss was about twice the original. In a recent phase III clinical
trial for overweight patients without diabetes, using Semalutide 2.4mg once a week, after
68 weeks of treatment, the body weight decreased by 14.9%, compared with 2.4% in the
control group.
GIP-related drug candidates

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The use of GIPR agonists in the treatment of obesity and T2D is questionable because of
the weakened insulin effect of GIP in T2D patients. In addition, clear preclinical evidence
suggests that GIPR antagonism can improve systemic energy and glucose metabolism,
possibly by improving central leptin sensitivity. However, long-acting (acyl) GIPR agonists
reduced the body weight in obese wild-type and GLP1R knockout mice, and GIP affected
body weight through the GIPR signaling pathway in the central nervous system.
Leptin and MC4 agonists
In 1994, people discovered leptin. The loss of leptin can cause severe metabolic disorders,
including extreme bulimia and lipodystrophy. However, although leptin supplementation is
effective for patients with congenital leptin deficiency, leptin has little effect on weight
reduction. Therefore, leptin as an independent therapy to treat obesity does not seem
promising, but its combined use with pramlintide can reduce the weight of overweight
people more than the treatment of two drugs alone.
In the past 30 years, a series of MC4R agonists have been developed, but MC4R agonists
that were discontinued in clinical trials due to poor efficacy or adverse reactions include
LY2112688 (Eli Lilly), MC4-NN-0453 ( Novo Nordisk), MK-0493 (Merck) and AZD2820
(AstraZeneca). In contrast, setmelanotide is a structurally related MC4R agonist, and
setmelanotide was well tolerated in phase III clinical trials without any major adverse
reactions. The FDA approved setmelanotide in November 2020 for the treatment of obese
patients with deficiencies in POMC, PCSK1, or LEPR.

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Figure 6: Effects of AOMs on weight loss in humans and rodents.
Amylin
Amylin (also known as IAPP) is a peptide co-secreted with insulin to reduce food intake
through the central control of satiety. Pramlintide is a synthetic analogue based on rat
amylin. The FDA has approved pramlintide for use in patients with T1D and
T2D. Importantly, the effect of pramlintide on reducing food intake and body weight is not
limited to patients with impaired glucose metabolism. Therefore, other amylin analogs with
improved pharmacokinetics are also considered as anti-obesity drugs.
Targeted mitochondrial uncouplers
BAM15 is a novel mitochondria-specific protonophore uncoupler that demonstrates similar
potency to DNP to increase energy expenditure. BAM15 is an oral drug that can
increase nutrient oxidation and reduce body fat without changing food intake. It has
been reported that mice treated with BAM15 are resistant to weight gain. BAM15 can
improve the insulin sensitivity in multiple tissues. It can enhance mitochondrial respiration
by continuously activating AMPK in vitro, improve insulin action and stimulate nutrient
intake. These results collectively indicate that mitochondrial uncoupling with BAM15 has a
powerful anti-obesity and insulin sensitization effect without affecting food intake.
GDF15
Macrophage inhibitory cytokine 1 (MIC1; also known as GDF15) continues to receive
attention as a target for obesity treatment. GDF15 is a divergent member of the
transforming growth factor-β (TGFβ) superfamily. Physiologically, GDF15 is expressed in
many tissues at a low concentration, but increases in expression with tissue damage,
cancer, metabolic diseases, CVD and inflammation.

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Exogenous administration of rDNA-derived GDF15 and its analogs can reduce the body
weight of diet-induced obese mice and non-human primates, indicating that it has a
stabilizing effect in energy homeostasis. Although the effects have been seen in animal
models, only human studies can determine whether GDF15 analogs are effective and
safe for weight loss.
Peptide tyrosine tyrosine
Peptide tyrosine tyrosine (PYY) is a member of the NPY family, and is co-secreted from
the intestinal L cells as PYY1-36, along with GLP-1. After being released, PYY1-36 is
rapidly cleaved by DPP-IV to its main active form PYY3-36, a high-affinity agonist of NPY
receptor type 2 (Y2R).
The ability of PYY3-36 to reduce food intake in rodents and humans has stimulated the
development of PYY3-36 analogs to treat obesity. Several long-acting PYY analogs
(NN9748 and NNC0165-1875) have completed the first phase of obesity treatment trials,
and NNC0165-1875 is currently undergoing a second phase of joint research with
Semalutide. In addition, Eli Lilly announced a phase I trial using PYY analogs to treat T2D.
Conclusion
The anti-obesity medications has a long history and the road is very tortuous. Obese
patients are often at high risk of vascular diseases and suffer from complications, which
complicate drug safety evaluation. In the future, a more comprehensive characterization
of patients will help provide direction for the advancement of the next generation of AOM.
Ongoing clinical research will determine whether the drug treatment of obesity can
achieve the same curative effect as bariatric surgery. The many prospects currently being
shown indicate that it is very possible to achieve this great goal.

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Reference：
https://www.nature.com/articles/s41573-021-00337-8
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