Design and synthesis of free fatty acid receptor modulators

Anders Højgaard Hansen

Research output: ThesisPh.D. thesis

Abstract

Evidence suggests that the short-chain free fatty acid receptors FFA2 and FFA3 are involved in regulation of metabolism and inflammatory responses, and as such these receptors represent potential drug targets for treatment of type 2 diabetes, obesity, and inflammatory diseases.
Inspired by a pyrrolidine-based agonist, Manuscript I and Chapter 2 describe the discovery of a potent and selective thiazolidine-based agonist with optimal lipophilic ligand efficiency. Attempts at replacing the thiazolidine with other scaffolds were realized, and one weakly potent agonist identified. Chapter 2 also describes the synthesis of a known FFA2 agonist, which was used as a tool for studying FFA2- mediated responses in neutrophils, as described in detail within Publication IV.
Chapter 3 describes the use of an alternative synthetic route to produce a β-amino acid building block central for synthesis of Euroscreen-type FFA2 antagonists. The second part presents scaffold simplification strategies, which led to the discovery of a new reasonably potent antagonist for FFA2. The last section describes the synthesis of a known azetidine-based FFA2 antagonist, whose effect on eosinophils is currently being investigated by our collaborators.
First part of Chapter 4 reports on the design, synthesis and application of the first potent FFA2 fluorescent tracer. Second part of Chapter 4 presents the design and synthesis of a reasonably potent photoswitchable agonist for FFA2.
Chapter 5 outlines selected parts of the work covered in Publication I. Based on the FFA1 crystal structure, a homology model of FFA2 was generated and applied for molecular docking experiments, which to some extent were able to rationalize binding data obtained using a radioactive FFA2 antagonist. Second part of Chapter 2 covers work conducted during my exchange stay at Queen’s University, Belfast in the group of Dr. Irina Tikhonova. An FFA2 homology model was used for structure-based virtual screening of commercial compound libraries. A selection of hits was purchased and tested in biological assays; unfortunately no active compounds were retrieved.
Chapter 6 covers parts of Publication III along with unpublished results. It reports on synthesis and pharmacological characterization of FFA3 allosteric modulators. Chapter 7 and Manuscript II describe a synthetic methodology where oxalyl chloride is employed as a convenient carbon monoxide source for practical alkoxycarbonylation of aryl bromides.  
Original languageEnglish
Awarding Institution
  • University of Southern Denmark
Supervisors/Advisors
  • Ulven, Trond, Principal supervisor
Date of defence18. Nov 2016
Place of PublicationOdense
Publisher
Publication statusPublished - 2017

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