title: Highly potent inhibitors of methionine aminopeptidase-2 based on a 1,2,4-triazole pharmacophore.
abstract: High-throughput screening for inhibitors of the human metalloprotease, methionine aminopeptidase-2 (MetAP2), identified a potent class of 3-anilino-5-benzylthio-1,2,4-triazole compounds. Efficient array and interative synthesis of triazoles led to rapid SAR development around the aniline, benzylthio, and triazole moeities. Evaluation of these analogs in a human MetAP2 enzyme assay led to the identification of several inhibitors with potencies in the 50-100 picomolar range. The deleterious effects on inhibitor potency by methylation of the anilino-triazole nitrogens, as well as the X-ray crystal structure of triazole 102 bound in the active site of MetAP2, confirm the key interactions between the triazole nitrogens, the active site cobalt atoms, and the His-231 side-chain. The structure has also provided a rationale for interpreting SAR within the triazole series. Key aniline (2-isopropylphenyl) and sulfur substituents (furanylmethyl) identified in the SAR studies led to the identification of potent inhibitors (103 and 104) of endothelial cell proliferation. Triazoles 103 and 104 also exhibited dose-dependent activity in an aortic ring tissue model of angiogenesis highlighting the potential utility of MetAP2 inhibitors as anticancer agents.
authors.affiliation: Department of Medicinal Chemistry, Enzymology, Oncology, and Structural Biology, GlaxoSmithkline, King of Prussia, PA 19406, USA. joseph.p.marino@gsk.com
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Marino
authors.forename: Paul W
authors.initials: PW
authors.lastname: Fisher
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Hofmann
authors.forename: Robert B
authors.initials: RB
authors.lastname: Kirkpatrick
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Janson
authors.forename: Randall K
authors.initials: RK
authors.lastname: Johnson
authors.forename: Chun
authors.initials: C
authors.lastname: Ma
authors.forename: Michael
authors.initials: M
authors.lastname: Mattern
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Meek
authors.forename: M Dominic
authors.initials: MD
authors.lastname: Ryan
authors.forename: Christina
authors.initials: C
authors.lastname: Schulz
authors.forename: Ward W
authors.initials: WW
authors.lastname: Smith
authors.forename: David G
authors.initials: DG
authors.lastname: Tew
authors.forename: Thaddeus A
authors.initials: TA
authors.lastname: Tomazek
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Veber
authors.forename: Wenfang C
authors.initials: WC
authors.lastname: Xiong
authors.forename: Yuuichi
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Keizo
authors.initials: K
authors.lastname: Yamashita
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Scott K
authors.initials: SK
authors.lastname: Thompson
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C524102:3-(2-(isopropyl)anilino)-5-(furan-2-ylmethylthio)-1,2,4-triazole; C524103:3-(2-(isopropyl)anilino)-5-(furan-3-ylmethylthio)-1,2,4-triazole; C524101:3-(2-(isopropyl)anilino)-5-(thiophen-2-ylmethylthio)-1,2,4-triazole; D020533:Angiogenesis Inhibitors; D005663:Furans; D013844:Thiazoles; D013876:Thiophenes; D014230:Triazoles; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases