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Research J. Science and Tech. 16(4): October - December, 2024
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ISSN 0975-4393 (Print) Available online at 2349-2988 (Online)
DOI:
Vol. 16| Issue-04| Research Journal of Science and Technology
October - December | 2024 Home page www.rjstonline.com
RESEARCH ARTICLE
Unlocking the potential: slu-pp-332 and the future of exercise Enhancement
and Metabolic health
Bhupendra M. Mahale1*, Akshata M. Girase2, Maheshwari M. Mahale3
1Pharmaceutics, Kavayitri Bahinabai Chaudhari NMU University, P.S.G.V.P. Mandal’s College of Pharmacy,
Shahada, Maharashtra, India.
2Pharmaceutical Quality Assurance, Kavayitri Bahinabai Chaudhari NMU University, P.S.G.V.P. Mandal’s College
of Pharmacy, Shahada, Maharashtra, India.
3Pharmaceutics, Dr. Babasaheb Ambedkar Technological University, Ahinsa Institute of Pharmacy, Dondaicha,
Maharashtra, India.
*Corresponding Author E-mail: bhupendramahale999@gmail.com
ABSTRACT:
The synthetic oestrogen receptor-related orphan receptor (ERR) agonist SLU-PP-332 exhibits promising potential in
revolutionizing fitness and weight loss strategies. Through its activation of ERRs, SLU-PP-332 enhances energy
expenditure, increases fatty acid oxidation, and reduces fat mass buildup. Studies indicate its ability to mimic exercise-
induced metabolic pathways, resulting in improved endurance and weight loss in mice. While long-term implications
are yet to be fully understood, initial trials show no significant adverse effects. SLU-PP-332 targets ERRs found in
various human organs, influencing vital metabolic processes. With implications for treating metabolic disorders like
obesity, type 2 diabetes, and heart failure, SLU-PP-332 emerges as a novel therapeutic agent. Its biological activity,
structure, and solubility data support its potential as a small molecule drug in endocrinology and metabolic diseases.
Further research is warranted to elucidate its long-term effects and refine its structure for future clinical applications
KEYWORDS: SLU-PP-332, ERR agonist, skeletal muscle, metabolic disorders, Exercise endurance, Therapeutic
potential
INTRODUCTION:
An enhanced aerobic activity mode is triggered by the synthetic oestrogen receptor-related orphan SLU-PP-332 is an
agonist of the receptor-related orphan receptor (ERR).. By enhancing a natural metabolic pathway that is usually
enhanced by exercise, this drug increases energy expenditure and speeds up the metabolism of body fat1. One of the
main tissues that adjusts to exercise is the skeletal muscle, which does so by changing its composition and metabolism
to accommodate the increased use. These physiological adaptations are driven by significant changes in skeletal
muscle gene and protein expression, which are brought on by physical exercise. Exercise improves muscle function
(strength), and following a single workout (acute exercise) or several exercise sessions (training), endurance can be
measured2.
Pyruvate dehydrogenase kinase 4 (Pdk4), an ERR target gene, is expressed more when SLU-PP-332 is present.
enhances cellular respiration and mitochondrial function in skeletal muscle cell lines, and increases mitochondrial
respiration in C2C12 myocytes.3 This medication acts on a class of proteins called extracellular reticulum (ERRs)
found in many human organs. These proteins drive some of the body's most important metabolic processes, including
those in the brain and heart tissue. Through its ability to stimulate the body's muscles during activity, the medication
Research J. Science and Tech. 16(4): October - December, 2024
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has the potential to revolutionise the future of fitness and aid in weight loss. SLU-PP-332 acts by activating ERRs,
which raises energy expenditure, increases fatty acid oxidation, and reduces the buildup of fat mass.4-5
Biological Activity:
The pan-estrogen receptor/ERR agonist SLU-PP-332 has EC50 values of 98, 230, and 430 nM for ERRα, ERRβ, and
ERRγ, respectively. SLUPP-332 increases mitochondrial activity and cellular respiration in skeletal muscle cell lines.
SLU-PP-332 has potential use in the study of metabolic diseases and improvement of muscular function. Molecular
Weight: 290.32
Formula: C18H14N2O2
Appearance: Solid
Color: White to off-white
SMILES: O=C (N/N=C/C1=CC=C2C=CC=CC2=C1) C3=CC=C (O) C=C3
Storage:
Powder
20°C
3 years
In
80°C
6 month
Solvent
20°C
1 month
Drug type: small molecule drug
Target: Estrogen related receptors
Mechanism: Estrogen related receptors agonist
Therapeutics area: Endocrinology and metabolic diseases
Activity indication: metabolic syndrome
Synonyms: SLU PP 332
Preferred IUPAC name: 4-hydroxy-N-[(Z)-naphthalen-2-ylmethyildeneamino] benzamide6-7
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough
for a few weeks during ordinary shipping and time spent in Customs.
Solubility: To be determined
Shelf Life: >2 years if stored properly
Drug Formulation: To be determined
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).8 Structure
of SLU PP-332:
Fig. 1: Chemical structure of SLU PP 3329
Benefits of exercise:
Apart from helping people lose weight, exercise also improves cardiovascular health, increases muscle strength and
endurance, and enhances mental well-being. Exercise can be done in a variety of contexts and can be customised to
meet the needs and preferences of the individual. Exercise can be a social activity that fosters support and social
contact.10-11
Long-term effects of taking SLU-PP-332:
The long-term effects of using SLU-PP-332 are unknown because the drug is currently in its early stages of
development. The next step is to improve its structure and make it into a medication candidate, ideally so that it may
be given as a tablet rather than an injection, as there haven't been any notable side effects from this treatment in the
mice experiment.12,13 The drug would then be examined for side effects in other animal models prior to beginning
human trials. Because of its capacity to lower weight, this drug may be used to treat ailments such as type 2 diabetes,
obesity, nonalcoholic fatty liver disease, heart failure, renal disease, and even cognitive dysfunction.14 Short-term
effects of taking SLU-PP-332:
Research J. Science and Tech. 16(4): October - December, 2024
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Since SLU-PP-332 is currently in its early phases of research and development, its immediate effects are still unknown.
Nevertheless, the drug had no adverse impact on mice's appetite or food intake during the experiment. On the other
hand, this substance improves an exercise-induced natural metabolic pathway, leading to higher energy expenditure
and better body fat metabolism. The medication induces a state in which the body mimics marathon training. This
chemical was given twice a day to obese mice for a month as part of the Billon et al investigation. Even though they
had the same amount of food, after 28 days they weighed less than rodents that did not receive the SLU-PP-332.
They dropped 12% of their body weight and acquired ten times less fat on average than mice who were not given any
treatment. The target of this novel chemical is a group of proteins known as ERRs, which activate a number of
metabolic pathways throughout the body, including those in the brain and heart tissues. Diseases like nonalcoholic
steatohepatitis, type 2 diabetes, obesity, heart failure, kidney disease, and even cognitive dysfunction may be treated
with the medication. The team has not noticed any serious adverse effects, but more research is needed on safety
issues.1,12,15,16
SLU-PP-332 Enhances Exercise Endurance in Mice:
To ascertain whether SLU-PP-332 might be utilised as a chemical probe to appraise the in vivo activation of ERR
function, we first evaluated in vivo exposure subsequent to intraperitoneal (i.p.) dosing in mice. After SLU-PP-332
(30 mg/kg, i.p.) was given to mice, muscle and plasma were extracted two and six hours later, and mass spectrometry
was used to analyse the results. After two hours of treatment, the plasma had lower levels of SLU-PP332 ( 0.2 μM)
than the skeletal muscle ( 0.6 μM). When SLU-PP-332 (50 mg/kg b.i.d., i.p.) was given to mice for 10 days, we saw
no overt toxicity, this is in line with typical electrolyte levels and full blood counts.17 Next, we looked at how long-
term SLU-PP-332 therapy affected the physiology and functionality of muscles. After receiving SLU-PP-332 for 15
days (50 mg/kg, b.i.d., i.p.) in three-month-old C57BL/6J mice, the histopathology of the quadriceps muscles was
examined. We raised the dosage to 50 mg/kg in the efficacy studies trial to increase medication exposure. We kept the
mice at thermoneutrality (30 °C) to prevent the impact of ERR on facultative thermogenesis and cold tolerance.
Unfixed muscle was used for histology, and the activity of succinate dehydrogenase (SDH) and hematoxylin and eosin
were stained. A more oxidative muscle phenotype (more SDH staining) was seen in mice treated with SLU-PP-332.18
Solubility Data for SLU PP-332:
Table 1: Solubility Data for SLU PP-332
Solvent
Max Conc. Mg/ml
Max conc. mM
Solubility
DMSO
29.03
100
Preparing stock solution for SLU-PP-332:
The batch molecular weight of 290.32 is the basis for the data that follows. Because of the degree of hydration, batch
specific molecular weight may differ, affecting the quantities of solvent needed to prepare stock solutions.19
Table 2: Preparing stock solution for SLU-PP-332
Concentration / solvent volume/ mass
1 mg
5 mg
10 mg
1 mM
3.44 mL
17.22 mL
34.44 mL
5 mM
0.69 mL
3.44 mL
6.89 mL
10 mM
0.34 mL
1.72 mL
3.44 mL
50 mM
0.07 mL
0.34 mL
0.69 mL
CONCLUSION:
The article's conclusion highlights how SLU-PP-332, a synthetic oestrogen receptor-related orphan receptor (ERR)
agonist, has the potential to transform fitness and help people lose weight by boosting metabolic pathways and aerobic
exercise. It draws attention to the capacity of SLU-PP-332 to stimulate ERRs, raise energy expenditure, and enhance
fatty acid oxidation, all of which may have therapeutic advantages for metabolic syndrome and its associated diseases,
such as type 2 diabetes and obesity. The short- and long-term effects of SLU-PP-332 are also covered, along with how
it affects mice's exercise endurance and safety profile. Overall, the results point to the potential of SLU-PP-332 as a
novel therapeutic agent for metabolic disorders and the need for more study and development in this area.
REFERENCE:
1. Billon C, Schoepke E, Avdagic A, Chatterjee A, Butler AA, Elgendy B, et al. A Synthetic ERR Agonist Alleviates Metabolic Syndrome. J
Pharmacol Exp Ther. 2023: JPET-AR-2023-001733. doi: 10.1124/ jpet.123.001733.
Research J. Science and Tech. 16(4): October - December, 2024
4
2. Egan, B.; Zierath, J. R. Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab. 2013; 17: 162− 184.
3. Ludvik B. Gewichtsreduktion durch Steigerung des Energieverbrauchs und der Thermogenese [Weight loss by increasing energy consumption
and thermogenesis]. Acta Med Austriaca. 1998; 25: 136-7
4. Lee J, Joh Y, Choi C, Kim K, Lee YH. A Combination of Soy Isoflavone and L-Carnitine Improves Running Endurance in Mice. Nutrients.
2023; 15: 3678. doi: 10.3390/nu15173678
5. Schoepke EL. Pharmacological Modulation of the Estrogen Related Receptors Alters Cellular Metabolism [dissertation]. Saint Louis
University; 2021.
6. https://www.medchemexpress.com/slu-pp-332.html
7. https://synapse.patsnap.com/drug/d49bda4b65c346de83f57ea1a317688d#overview
8. https://www.medkoo.com/products/53978
9. https://en.wikipedia.org/wiki/SLU-PP-332#/media/File:SLU-PP-332_structure.png
10. Sharma A, Madaan V, Petty FD. Exercise for mental health. Prim Care Companion J Clin Psychiatry. 2006; 8: 106. doi:
10.4088/pcc.v08n0208a.
11. Committee on Physical Activity and Physical Education in the School Environment; Food and Nutrition Board; Institute of Medicine; Kohl
HW III, Cook HD, editors. Educating the Student Body: Taking Physical Activity and Physical Education to School. Washington (DC):
National Academies Press (US); 2013 Oct 30. 3, Physical Activity and Physical Education: Relationship to Growth, Development, and Health.
Available from: https://www.ncbi.nlm.nih.gov/books/NBK201497/.
12. Billon C, Sitaula S, Banerjee S, Welch R, Elgendy B, Hegazy L, et al. Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic
Exercise Response and Enhances Exercise Capacity. ACS Chem Biol. 2023; 18: 756-771. doi: 10.1021/ acschembio.2c00720
13. Kim WY, Sharpless NE. Drug efficacy testing in mice. Curr Top Microbiol Immunol. 2012; 355: 19-38. doi: 10.1007/82_2011_160.
14. Hanson AM, Perera KLIS, Kim J, Pandey RK, Sweeney N, Lu X, et al. A-C Estrogens as Potent and Selective Estrogen ReceptorBeta Agonists
(SERBAs) to Enhance Memory Consolidation under Low-Estrogen Conditions. J Med Chem. 2018; 61: 4720- 4738. doi:
10.1021/acs.jmedchem.7b01601.
15. Liu X, Zhang Z, Song Y, Xie H, Dong M. An update on brown adipose tissue and obesity intervention: Function, regulation, and therapeutic
implications. Front Endocrinol (Lausanne). 2023; 13: 1065263. doi: 10.3389/fendo.2022.1065263.
16. Smith RL, Soeters MR, Wüst RCI, Houtkooper RH. Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health
and Disease. Endocr Rev. 2018; 39: 489-517. doi: 10.1210/er.2017-00211
17. Otto, G. P.; Rathkolb, B.; Oestereicher, M. A.; Lengger, C. J.; Moerth, C.; Micklich, K.; Fuchs, H.; Gailus-Durner, V.; Wolf, E.; Hrabe de
Angelis, M. Clinical Chemistry Reference Intervals for C57BL/6J, C57BL/6N, and C3HeB/FeJ Mice (Mus musculus). J. Am. Assoc. Lab.
Anim. Sci. 2016; 55: 375−386.
18. Villena, J. A.; Hock, M. B.; Chang, W. Y.; Barcas, J. E.; Giguere, V.; Kralli, A. Orphan nuclear receptor estrogen-related receptor alpha is
essential for adaptive thermogenesis. Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 1418−1423
19. https://www.tocris.com/products/slu-pp-332_8112
Received on 09.01.2023 Modified on 22.03.2023
Accepted on 08.04.2023 ©A&V Publications All right reserved
Research J. Science and Tech. 2024; 16(4):. DOI:
