Removal of the phosphate group in mechanism-based inhibitors of inositol monophosphatase leads to unusual inhibitory activity

Miller, David James, Bashir-Uddin Surfraz, M., Akhtar, Mahmoud, Gani, David and Allemann, Rudolf Konrad ORCID: https://orcid.org/0000-0002-1323-8830 2004. Removal of the phosphate group in mechanism-based inhibitors of inositol monophosphatase leads to unusual inhibitory activity. Organic & Biomolecular Chemistry 2 (5) , pp. 671-688. 10.1039/b312808c

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Abstract

Inositol monophosphatase is widely held to be the therapeutic target for inhibition by lithium ion in the treatment of bipolar disorder. In a continued effort to improve the bioavailability of alternative inhibitors, we have designed and tested two new series of compounds; phosphonates and product-like mimics. Phosphonate substrate mimics were competitive inhibitors of reduced potency as compared to phosphate based inhibitors. Product mimics however, showed various inhibitory modes of action. The 6-butylamino derivative 6p was an uncompetitive inhibitor when acting alone (Ki = 0.3 mM) but displayed non-competitive inhibition in the presence of inorganic phosphate. This compound represents a new lead in the search for a viable replacement for lithium ion therapy.

Item Type:	Article
Status:	Published
Schools:	Chemistry Cardiff Catalysis Institute (CCI)
Subjects:	Q Science > QD Chemistry
Publisher:	Royal Society of Chemistry
ISSN:	1477-0520
Last Modified:	03 Dec 2022 11:11
URI:	https://orca.cardiff.ac.uk/id/eprint/12498

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