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Structure-activity relationships for lipoprotein lipase agonists that lower plasma triglycerides in vivo
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
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2015 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 103, 191-209 p.Article in journal (Refereed) Published
Abstract [en]

The risk of cardiovascular events increases in individuals with elevated plasma triglyceride (TG) levels, therefore advocating the need for efficient TG-lowering drugs. In the blood circulation, TG levels are regulated by lipoprotein lipase (LPL), an unstable enzyme that is only active as a non-covalently associated homodimer. We recently reported on a N-phenylphthalimide derivative (1) that stabilizes LPL in vitro, and moderately lowers triglycerides in vivo (Biochem. Biophys. Res. Common. 2014, 450, 1063). Herein, we establish structure activity relationships of 51 N-phenylphthalimide analogs of the screening hit 1. In vitro evaluation highlighted that modifications on the phthalimide moiety were not tolerated and that lipophilic substituents on the central phenyl ring were functionally essential. The substitution pattern on the central phenyl ring also proved important to stabilize LPL However, in vitro testing demonstrated rapid degradation of the phthalimide fragment in plasma which was addressed by replacing the phthalimide scaffold with other heterocyclic fragments. The in vitro potency was retained or improved and substance 80 proved stable in plasma and efficiently lowered plasma TGs in vivo. 2015 The Authors. Published by Elsevier Masson SAS.

Place, publisher, year, edition, pages
Elsevier, 2015. Vol. 103, 191-209 p.
Keyword [en]
Lipoprotein lipase, LPL, Triglyceride, Structure-activity relationship, Agonist
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:umu:diva-111481DOI: 10.1016/j.ejmech.2015.08.058ISI: 000363344700015PubMedID: 26355531OAI: oai:DiVA.org:umu-111481DiVA: diva2:877887
Available from: 2015-12-08 Created: 2015-11-13 Last updated: 2015-12-08Bibliographically approved

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Caraballo, RemiLarsson, MikaelNilsson, Stefan K.Ericsson, MadeleneQian, WeixingTran, Nam Phuong NguyenKindahl, TomasSaar, ValeriaOlivecrona, GunillaEnquist, Per-AndersElofsson, Mikael
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Department of ChemistryPhysiological chemistryUmeå Centre for Microbial Research (UCMR)
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European Journal of Medicinal Chemistry
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ReferencesLink to record
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