Thoma, Gebhard, Vangrevelinghe, Eric, Luneau, Alexandre, Piechon, Philippe, Beerli, Christian and Zerwes, Hans Guenter (2023) Novel Concept for Super-Soft Topical Drugs: Deactivation by an Enzyme-Induced Switch into an Inactive Conformation. ACS medicinal chemistry letters, 14. ISSN 1948-5875

Abstract

We present a novel concept for the design of soft topical drugs. Enzymatic cleavage of the carbonate ester of the potent pan Janus kinase (JAK) inhibitor 2 releases hydroxypyridine 3. Due to hydroxypyridine-pyridone tautomerism, 3 undergoes a rapid conformational change preventing the compound to assume the bioactive conformation required for binding to JAK kinases. We demonstrate that the hydrolysis in human blood and the subsequent shape change lead to the deactivation of 2.

Item Type:	Article
Keywords:	Jak, soft drug, topical
Date Deposited:	13 Jul 2023 00:45
Last Modified:	13 Jul 2023 00:45
URI:	https://oak.novartis.com/id/eprint/50267