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Bioorg Med Chem Lett. 2017 Feb 1;27(3):551-556. doi: 10.1016/j.bmcl.2016.12.019. Epub 2016 Dec 8.

Novel reversible methionine aminopeptidase-2 (MetAP-2) inhibitors based on purine and related bicyclic templates.

Author information

1
Discovery Technologies, Merck KGaA, Frankfurter Str. 250, D-64293 Darmstadt, Germany. Electronic address: timo.heinrich@merckgroup.com.
2
Discovery Technologies, Merck KGaA, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
3
Process Technologies, Merck KGaA, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
4
Drug Disposition, Merck KGaA, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
5
In Vivo Pharmacology, Merck KGaA, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
6
Project Management, Merck KGaA, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
7
Cellular Pharmacology, Merck KGaA, Frankfurter Str. 250, D-64293 Darmstadt, Germany.

Abstract

The natural product fumagillin 1 and derivatives like TNP-470 2 or beloranib 3 bind to methionine aminopeptidase 2 (MetAP-2) irreversibly. This enzyme is critical for protein maturation and plays a key role in angiogenesis. In this paper we describe the synthesis, MetAP-2 binding affinity and structural analysis of reversible MetAP-2 inhibitors. Optimization of enzymatic activity of screening hit 10 (IC50: 1μM) led to the most potent compound 27 (IC50: 0.038μM), with a concomitant improvement in LLE from 2.1 to 4.2. Structural analysis of these MetAP-2 inhibitors revealed an unprecedented conformation of the His339 side-chain imidazole ring being co-planar sandwiched between the imidazole of His331 and the aryl-ether moiety, which is bound to the purine scaffold. Systematic alteration and reduction of H-bonding capability of this metal binding moiety induced an unexpected 180° flip for the triazolo[1,5-a]pyrimdine bicyclic template.

KEYWORDS:

MetAP2; Metalloprotease; Methionine aminopeptidase 2; Purine

PMID:
27998678
DOI:
10.1016/j.bmcl.2016.12.019
[Indexed for MEDLINE]

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