???? Do you want to get fit without dieting or exercising by tricking your body? This sounds like sci-fi, or like a scammy ad for a fat burning supplement. However, given recent advances in exercise mimetics and strong momentum behind treating obesity pharmacologically (most notably, semaglutide – Ozempic/Wegovy and tirzepatide – Mounjaro/Zepbound), this idea could reality sooner than some expect.
???? In this video we will discover SLU-PP-332, a small molecule that mimics endurance training and dieting in mice – without exercise or eating less. We will cover 1) the biochemical basics of exercise mimetics and mechanisms of action, 2) take a look at pre-clinical data of different compounds, and 3) as always, review chemistry concepts.
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00:00 Trick your body into losing weight – is it possible?
01:22 Obesity problem, logic behind using drugs and limitations
02:31 GLP1 agonists
03:01 Exercise mimetic basics
04:04 Resveratrol’s exercise mimicry, health benefits and unexpected effects
06:03 ERR up/downregulation can trigger major effects – transgenic and knock-out mice
09:18 Drug design logic behind SLU-PP-332
11:02 Organic synthesis of SLU-PP-332 (too easy)
11:32 Molecular, structural, physiological and metabolic effects of SLU-PP-332
15:05 Outlook and conclusion
Key references:
– PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism | Oxidative Medicine and Cellular Longevity, 2020, 1452696
– Caloric restriction and exercise “mimetics’’: Ready for prime time? | Pharmacological Research 2016, 103, 158
– Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha | Cell 2006, 127, 1109
– Distribution and Effects of Estrogen Receptors in Prostate Cancer: Associated Molecular Mechanisms | Frontiers in Endocrinology 2022, 12, 811578
– Identification and structure-activity relationship of phenolic acyl hydrazones as selective agonists for the estrogen-related orphan nuclear receptors ERRbeta and ERRgamma | J Med Chem 2005, 48, 3107
– Exercise and PGC-1 alpha-Independent Synchronization of Type I Muscle Metabolism and Vasculature by ERR gamma | Cell Metabolism 2011, 13, 283
– Estrogen-related receptor-α coordinates transcriptional programs essential for exercise tolerance and muscle fitness | Mol Endocrinol 2014, 28, 2060
– Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic Exercise Response and Enhances Exercise Capacity | ACS Chem. Biol. 2023, 18, 756
– A Synthetic ERR Agonist Alleviates Metabolic Syndrome | J. Pharmacol. Exp. Ther. 2023, 001733
Another related SLU-PP compound with more chemistry information behind it:
Development and pharmacological evaluation of a new chemical series of potent pan-ERR agonists, identification of SLU-PP-915 | Eur J Med Chem 2023, 258, 115582
Some recommended books on organic synthesis:
– Clayden, Greeves, Warren; Organic Chemistry (basic organic chemistry knowledge)
– Wyatt, Warren; Organic Synthesis: The Disconnection Approach (excellent introduction to retrosynthesis)
– Kurti, Czako; Strategic Applications of Named Reactions in Organic Synthesis (extensive toolkit of functional group reactions and applications thereof with common conditions)
– Nicolaou; Classics in Total Synthesis 1-3 (the ultimate total synthesis trilogy)
– Nicolaou; Molecules That Changed the World (the world’s most important molecules and their impact on everyday life)
– Carreira, Kvaerno; Classics in Stereoselective Synthesis (compilation of the groundbreaking methods of stereoselective synthesis and application to synthesis of stereochemically complex structures)
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