Novel inhibitors

Abstract

The invention relates to a compound of formula (I): A-B-D-E (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, wherein: A is selected from monocyclic and bicyclic heteroaryl, which may independently substituted by alkyl or amino; B is selected from alkyl, heteroalkyl, alkyl-amino, aryl, heteroaryl, cycloalkyl, heterocyclyl and alkylene, wherein said groups may independently be substituted by alkyl; D is selected from aryl-amino, heteroaryl-amino, cycloalkyl-amino, heterocyclyl, heterocyclyl-amino, urea, thioamide, thiourea, sulfonamide, sulfoximine and sulfamoyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups may independently be substituted; and E is selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups may independently be substituted. The compounds of formula (I) are inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5). QC catalyzes the intramolecular cyclization of N-terminal glutamine residues into pyroglutamic acid (5-oxo-prolyl, pGlu*) under liberation of ammonia and the intramolecular cyclization of N-terminal glutamate residues into pyroglutamic acid under liberation of water.

Description

technical field [0001] The present invention relates to novel heterocyclic derivatives as inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5). QC catalyzes the intramolecular cyclization of N-terminal glutamine residues to pyroglutamic acid (5-oxo-prolyl, pGlu*) upon release of ammonia, and the N-terminal glutamic acid residues upon release of water. Intramolecular cyclization to pyroglutamic acid. Background technique [0002] Glutaminyl cyclase (QC, EC 2.3.2.5) catalyzes the intramolecular cyclization of N-terminal glutamine residues to pyroglutamate (pGlu*), releasing ammonia. QC was first isolated from the latex of the tropical plant Carica papaya by Messer in 1963 (Messer, M.1963 Nature 4874, 1299). After 24 years, a corresponding enzymatic activity was found in animal pituitary glands (Busby, W.H.J. et al. 1987 J Biol Chem 262, 8532-8536; Fischer, W.H. and Spiess, J. 1987 Proc Natl Acad Sci USA 84, 3628-3632). For mammalian QC, the conversion of Gln to pGlu by QC can ...

AI Technical Summary

Problems solved by technology

However, comparison of the primary structure of the QC from papaya with that of the highly conserved QC from mammals did not reveal any sequence homology (Dahl, S.W. et al. 2000 Protein Expr Purif 20, 27-36)

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