This Drug Synthesis is Literally Breathtaking | Medicinal Chemistry & Organic Synthesis

This molecule might look like any other ‘flat drug’ – but there’s a mystery hidden behind its synthesis! Coupled with the fact that it showed promise in asthma due to its novel mechanism, you could say that it’s breath-taking (actually more like breath-giving, but I figured no one will understand this).
Watch this video to learn more about organic synthesis, drug development and more!

00:00 A breath-taking synthesis
00:23 Structure of our target molecule
01:37 Intro to PI3K enzymes and inhibitor drugs
03:41 Levels of chemistry sophistication
05:09 Retrosynthesis of AZD8154 and overview
05:57 Forward synthesis # 1
07:26 What was the problem?
08:19 Forward synthesis # 2
11:10 How legit is the solution?
12:03 FDA stance on PI3K inhibitors, and conclusion

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Key references:
– Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma | J. Med. Chem. 2021, 64, 8053
– Class I Phosphoinositide 3-Kinase PIK3CA/p110α and PIK3CB/p110β Isoforms in Endometrial Cancer | Int. J. Mol. Sci. 2018, 19, 3931
– The Pathogenic Role of PI3K/AKT Pathway in Cancer Onset and Drug Resistance: An Updated Review | Cancers 2021, 13, 3949
– Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3-Kinase (PI3K)-γ Inhibitors | J. Med. Chem. 2018, 61, 5435
– An Intramolecular Diels–Alder Approach to the Isoindolinone Core of AZD8154 | doi.org/10.1021/acs.oprd.3c00507
– Selection and Development of the Manufacturing Route for EP1 Antagonist GSK269984B | Org. Process Res. Dev. 2010, 14, 820
– Characterisation of pharmacokinetics, safety and tolerability in a first-in-human study for AZD8154, a novel inhaled selective PI3Kγδ dual inhibitor targeting airway inflammatory disease | Br J Clin Pharmacol. 2022, 88, 260
– Copanlisib for treatment of B-cell malignancies: the development of a PI3K inhibitor with considerable differences to idelalisib | Drug Des Devel Ther 2018, 12, 2577

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