title: Novel reversible methionine aminopeptidase-2 (MetAP-2) inhibitors based on purine and related bicyclic templates.
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.
authors.affiliation: Discovery Technologies, Merck KGaA, Frankfurter Str. 250, D-64293 Darmstadt, Germany. Electronic address: timo.heinrich@merckgroup.com.
authors.forename: Timo
authors.initials: T
authors.lastname: Heinrich
authors.affiliation: Discovery Technologies, Merck KGaA, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Buchstaller
authors.affiliation: Process Technologies, Merck KGaA, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
authors.forename: Bertram
authors.initials: B
authors.lastname: Cezanne
authors.affiliation: Drug Disposition, Merck KGaA, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Rohdich
authors.affiliation: Discovery Technologies, Merck KGaA, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Bomke
authors.affiliation: In Vivo Pharmacology, Merck KGaA, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
authors.forename: Manja
authors.initials: M
authors.lastname: Friese-Hamim
authors.affiliation: Discovery Technologies, Merck KGaA, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
authors.forename: Mireille
authors.initials: M
authors.lastname: Krier
authors.affiliation: Project Management, Merck KGaA, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Knöchel
authors.affiliation: Discovery Technologies, Merck KGaA, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
authors.forename: Djordje
authors.initials: D
authors.lastname: Musil
authors.affiliation: Discovery Technologies, Merck KGaA, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Leuthner
authors.affiliation: Cellular Pharmacology, Merck KGaA, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Zenke
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D063208:Methionyl Aminopeptidases; D008958:Models, Molecular; D015394:Molecular Structure; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D006023:Glycoproteins; D011687:Purines; D011743:Pyrimidines; D000626:Aminopeptidases; C081311:METAP2 protein, human; D063208:Methionyl Aminopeptidases; C030985:purine
keywords: MetAP2; Metalloprotease; Methionine aminopeptidase 2; Purine