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

• Published in: Bioorganic & medicinal chemistry letters 2017-02, Vol.27 (3), p.551-556
• Main Authors: Heinrich, Timo, Buchstaller, Hans-Peter, Cezanne, Bertram, Rohdich, Felix, Bomke, Jörg, Friese-Hamim, Manja, Krier, Mireille, Knöchel, Thorsten, Musil, Djordje, Leuthner, Birgitta, Zenke, Frank
• Format: Article
• Language: English
• Subjects: Aminopeptidases - antagonists & inhibitors; Aminopeptidases - metabolism; Dose-Response Relationship, Drug; Glycoproteins - antagonists & inhibitors; Glycoproteins - metabolism; Humans; Metalloprotease; MetAP2; Methionine aminopeptidase 2; Models, Molecular; Molecular Structure; Purine; Purines - chemical synthesis; Purines - chemistry; Purines - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.12.019

Both, the purine and the triazolopyrimidine based MetAP-2 inhibitors coordinate the manganese ions in the active site but the 5/6 membered bicyclic ring system is flipped by 180°C. When binding the latter the imidazole side chain of His339 is pushed out of its conformation with the purine MetAP-2 inhibitor. [Display omitted] 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.