Åsmund Kaupang

• Kaupang, Åsmund & Hansen, Trond Vidar (2020). The PPAR Ω Pocket: Renewed Opportunities for Drug Development. PPAR Research.  ISSN 1687-4757.  2020 . doi: 10.1155/2020/9657380 Show summary

  The past decade of PPARγ research has dramatically improved our understanding of the structural and mechanistic bases for the diverging physiological effects of different classes of PPARγ ligands. The discoveries that lie at the heart of these developments have enabled the design of a new class of PPARγ ligands, capable of isolating central therapeutic effects of PPARγ modulation, while displaying markedly lower toxicities than previous generations of PPARγ ligands. This review examines the emerging framework around the design of these ligands and seeks to unite its principles with the development of new classes of ligands for PPARα and PPARβ/δ. The focus is on the relationships between the binding modes of ligands, their influence on PPAR posttranslational modifications, and gene expression patterns. Specifically, we encourage the design and study of ligands that primarily bind to the Ω pockets of PPARα and PPARβ/δ. In support of this development, we highlight already reported ligands that if studied in the context of this new framework may further our understanding of the gene programs regulated by PPARα and PPARβ/δ. Moreover, recently developed pharmacological tools that can be utilized in the search for ligands with new binding modes are also presented.

• Kaupang, Åsmund; Laitinen, Tuomo; Poso, Antti & Hansen, Trond Vidar (2017). Structural review of PPARγ in complex with ligands: Cartesian- and dihedral angle principal component analyses of X-ray crystallographic data. Proteins: Structure, Function, and Bioinformatics.  ISSN 0887-3585.  85(9), s 1684- 1698 . doi: 10.1002/prot.25325 Full text in Research Archive.
• Kaupang, Åsmund; Kase, Eili Tranheim; Vo, Cecilie Xuan Trang; Amundsen, Marthe; Vik, Anders & Hansen, Trond Vidar (2016). Synthesis of 5-trifluoromethyl-2-sulfonylpyridine PPARβ/δ antagonists: Effects on the affinity and selectivity towards PPARβ/δ. Bioorganic & Medicinal Chemistry.  ISSN 0968-0896.  24(2), s 247- 260 . doi: 10.1016/j.bmc.2015.12.012
• Kaupang, Åsmund; Hildonen, Siri; Halvorsen, Trine Grønhaug; Mortén, Magnus; Vik, Anders & Hansen, Trond Vidar (2015). Involvement of covalent interactions in the mode of action of PPARβ/δ antagonists. RSC Advances.  ISSN 2046-2069.  5(93), s 76483- 76490 . doi: 10.1039/c5ra15707b
• Kaupang, Åsmund; Paulsen, Steinar Martin; Steindal, Calin Constantin; Ravna, Aina Westrheim; Sylte, Ingebrigt; Halvorsen, Trine Grønhaug; Thoresen, G. Hege & Hansen, Trond Vidar (2015). Synthesis, biological evaluation and molecular modeling studies of the PPARβ/δ antagonist CC618. European Journal of Medicinal Chemistry.  ISSN 0223-5234.  94, s 229- 236 . doi: 10.1016/j.ejmech.2015.03.006 Full text in Research Archive.
• Gorbitz, Carl Henrik; Bonge-Hansen, Tore & Kaupang, Åsmund (2013). N,N'-Bis(2-diazoacetyl)piperazine. Acta Crystallographica Section E: Structure Reports Online.  ISSN 1600-5368.  69(8), s o1241 . doi: 10.1107/S1600536813018801
• Kaupang, Åsmund & Bonge-Hansen, Tore (2013). α-Bromodiazoacetamides – a new class of diazo compounds for catalyst-free, ambient temperature intramolecular C–H insertion reactions. Beilstein Journal of Organic Chemistry.  ISSN 2195-951X.  9, s 1407- 1413 . doi: 10.3762/bjoc.9.157
• Kaupang, Åsmund; Gorbitz, Carl Henrik & Bonge-Hansen, Tore (2013). A solid-state oxidation of 1,1,3,3-tetramethylguanidinium 4-methylbenzenesulfinate to 1,1,3,3-tetramethylguanidinium 4-methylbenzenesulfonate. Acta Crystallographica Section C: Crystal Structure Communications.  ISSN 0108-2701.  69, s 778- + . doi: 10.1107/S0108270113015011
• Kaupang, Åsmund; Gorbitz, Carl Henrik & Hansen, Tore (2011). 2-Diazo-1-(1,1-dioxothiomorpholin-4-yl)ethanone. Acta Crystallographica Section E: Structure Reports Online.  ISSN 1600-5368.  67, s O1844- U2037 . doi: 10.1107/S1600536811023774
• Kaupang, Åsmund; Gorbitz, Carl Henrik & Hansen, Tore (2010). tert-Butyl 4-(2-diazoacetyl)piperazine-1-carboxylate. Acta Crystallographica Section E: Structure Reports Online.  ISSN 1600-5368.  66, s O2199- U467 . doi: 10.1107/S1600536810016211
• Kaupang, Åsmund; Bolsones, M; Gamadeku, T; Hansen, Tore; Hennum, MJ & Gorbitz, Carl Henrik (2008). 2SR,3RS)-Benzyl[4-chloro-1-(4-chlorophenyl)-1-methoxycarbonyl-2-butyl]ammonium chloride. Acta Crystallographica Section E: Structure Reports Online.  ISSN 1600-5368.  64, s O2038- U4798 . doi: 10.1107/S1600536808030742

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• Kaupang, Åsmund (2016). Development of PPAR Modulators and Investigations on their Mode of Action. Full text in Research Archive. Show summary

  The peroxisome proliferator-activated receptors (PPARα, PPARβ/δ and PPARγ) are nuclear receptors whose target genes have fundamental roles in human health and disease. The PPAR-regulated expression of these genes influences a range of physiological processes, including cell differentiation and proliferation, inflammation and lipid metabolism. Thus, the ligand-dependent modulation of PPAR activity is a potential point of pharmacological intervention in e.g. metabolic-, neurodegenerative- and dermatologic diseases. Recent reports on the involvement of PPARβ/δ in the pathophysiologies of breast cancer and psoriasis, highlight this PPAR subtype as a target of particular interest. The effects of agonistic ligands on PPAR target gene expression have been studied for nearly two decades and a structurally diverse collection of agonists has been reported. In contrast, fewer PPAR antagonists have been reported and the knowlegde about their various modes of action is less developed than that of agonists. In this thesis, the development of new members of a class of covalent PPARβ/δ antagonists is presented. Our studies demonstrate that the selectivity of the new antagonists for PPARβ/δ could be increased through subtle modifications of the structure of a previously reported antagonist, without affecting its mode of action. In extension of these studies, an investigation into the modes of action of the reported antagonistic ligands of PPARβ/δ was undertaken. In this study, an emphasis was put on the possible involvement of covalent bond formation between PPARβ/δ and the antagonistic ligands. Through a series of chemical and biological assays, it could be demonstrated that the reported antagonistic ligands differ markedly in their modes of action. Our results thus contribute to a more nuanced classification of the studied PPARβ/δ ligands. Finally, the recent dicovery of a novel post-translational modification of PPARγ, has impacted on the understanding of the beneficial effects of PPARγ agonists as drugs to treat metabolic diseases. The nature of the ligand-dependent inhibition of this undesired regulatory event, has shifted the focus of PPARγ ligand development away from full agonists, towards the development of partial- and non-agonists. The large body of structural data from x-ray crystallography on PPARγ in complex with ligands displaying a diverse set of binding modes, permitted a collective analysis of these data, aiming to identify structural trends in the influences of the ligands on PPARγ. Our study employed principal component analyses of the atomic coordinates and dihedral angles of PPARγ. The results of this investigation demonstrate a separation of the PPARγ structures, corresponding to a varying degree of stabilization of a region of the protein, known to be important for the undesired biological effects of full agonists. Thus, our analysis provides a mapping of the PPARγ structures with potential utility in the development of new partial- and non-agonistic PPARγ ligands.

• Kaupang, Åsmund; Hildonen, Siri; Halvorsen, Trine Grønhaug; Mortén, Magnus; Vik, Anders & Hansen, Trond Vidar (2015). Investigations on the covalent antagonistic modulation of PPARβ/δ.
• Kaupang, Åsmund; Laitinen, Tuomo; Poso, Antti & Hansen, Trond Vidar (2013). Vibrational fingerprinting of hPPARγ in complex with ligands – application to the natural product (-)-mucosin.
• Kaupang, Åsmund; Laitinen, Tuomo; Vik, Anders; Poso, Antti & Hansen, Trond Vidar (2013). Molecular modelling and synthesis of putative high-affinity inhibitors of hPPARδ.

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