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 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] benzamide^6-7

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:

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-PP-332 (∼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.

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 21.06.2024 Revised on 23.07.2024

Accepted on 20.08.2024 Published on 14.12.2024

Available online on December 05, 2024

Research J. Science and Tech. 2024; 16(4):321-324.

DOI: 10.52711/2349-2988.2024.00047

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.