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Structure-activity relationships for lipoprotein lipase agonists that lower plasma triglycerides in vivo
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
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2015 (Engelska)Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 103, s. 191-209Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Elsevier, 2015. Vol. 103, s. 191-209
Nyckelord [en]
Lipoprotein lipase, LPL, Triglyceride, Structure-activity relationship, Agonist
Nationell ämneskategori
Kemi
Identifikatorer
URN: urn:nbn:se:umu:diva-111481DOI: 10.1016/j.ejmech.2015.08.058ISI: 000363344700015PubMedID: 26355531OAI: oai:DiVA.org:umu-111481DiVA, id: diva2:877887
Tillgänglig från: 2015-12-08 Skapad: 2015-11-13 Senast uppdaterad: 2018-06-07Bibliografiskt granskad

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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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Caraballo, RemiLarsson, MikaelNilsson, Stefan K.Ericsson, MadeleneQian, WeixingTran, Nam Phuong NguyenKindahl, TomasSaar, ValeriaOlivecrona, GunillaEnquist, Per-AndersElofsson, Mikael
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Kemiska institutionenFysiologisk kemiUmeå Centre for Microbial Research (UCMR)
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European Journal of Medicinal Chemistry
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