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

• Published in: Bioorganic & medicinal chemistry letters Vol. 27; no. 3; pp. 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: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.02.2017; Elsevier
• Subjects: Aminopeptidases - antagonists & inhibitors; Aminopeptidases - metabolism; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Glycoproteins - antagonists & inhibitors; Glycoproteins - metabolism; Humans; Life Sciences & Biomedicine; Metalloprotease; MetAP2; Methionine aminopeptidase 2; Models, Molecular; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Purine; Purines - chemical synthesis; Purines - chemistry; Purines - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Science & Technology; Structure-Activity Relationship; Methionine aminopeptidase 2; Metalloprotease; Purine; MetAP2; ANGIOGENESIS; PHOSPHORYLATION; FUMAGILLIN; PROLIFERATION; SUPPRESSION; CANCER; P67; TNP-470; TUMOR-GROWTH; DERIVATIVES
• 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.