title: Synthesis of quaternary α-amino acid-based arginase inhibitors via the Ugi reaction.
abstract: The Ugi reaction has been successfully applied to the synthesis of novel arginase inhibitors. In an effort to decrease conformational flexibility of the previously reported series of 2-amino-6-boronohexanoic acid (ABH) analogs 1, we designed and synthesized a series of compounds, 2, in which a piperidine ring is linked directly to a quaternary amino acid center. Further improvement of in vitro activity was achieved by adding two carbon bridge in the piperidine ring, that is, tropane analogs 11. These improvements in activity are rationalized by X-ray crystallography analysis, which show that the tropane ring nitrogen atom moves into direct contact with Asp202 (arginase II numbering). The synthetic routes described here enabled the design of novel arginase inhibitors with improved potency and markedly different physico-chemical properties compared to ABH. Compound 11c represents the most in vitro active arginase inhibitor reported to date.
authors.affiliation: Institutes for Pharmaceutical Discovery, 23 Business Park Drive, Branford, CT, United States. golebiowski.a@gmail.com
authors.forename: Adam
authors.initials: A
authors.lastname: Golebiowski
authors.forename: Darren
authors.initials: D
authors.lastname: Whitehouse
authors.forename: R Paul
authors.initials: RP
authors.lastname: Beckett
authors.forename: Michael
authors.initials: M
authors.lastname: Van Zandt
authors.forename: Min Koo
authors.initials: MK
authors.lastname: Ji
authors.forename: Todd R
authors.initials: TR
authors.lastname: Ryder
authors.forename: Erik
authors.initials: E
authors.lastname: Jagdmann
authors.forename: Monica
authors.initials: M
authors.lastname: Andreoli
authors.forename: Yung
authors.initials: Y
authors.lastname: Lee
authors.forename: Ryan
authors.initials: R
authors.lastname: Sheeler
authors.forename: Bruce
authors.initials: B
authors.lastname: Conway
authors.forename: Jacek
authors.initials: J
authors.lastname: Olczak
authors.forename: Marzena
authors.initials: M
authors.lastname: Mazur
authors.forename: Wojciech
authors.initials: W
authors.lastname: Czestkowski
authors.forename: Wieslawa
authors.initials: W
authors.lastname: Piotrowska
authors.forename: Alexandra
authors.initials: A
authors.lastname: Cousido-Siah
authors.forename: Francesc X
authors.initials: FX
authors.lastname: Ruiz
authors.forename: Andre
authors.initials: A
authors.lastname: Mitschler
authors.forename: Alberto
authors.initials: A
authors.lastname: Podjarny
authors.forename: Hagen
authors.initials: H
authors.lastname: Schroeter
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000614:Aminocaproates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001896:Boron Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: C121228:2-amino-6-boronohexanoic acid; D000596:Amino Acids; D000614:Aminocaproates; D001896:Boron Compounds; D004791:Enzyme Inhibitors; D001119:Arginase
keywords: ABH; Arginase inhibitor; Boronic acid; Metalloenzyme; Ugi reaction