Structure-activity relationships for lipoprotein lipase agonists that lower plasma triglycerides in vivo.
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. Commun.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.
Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
Rémi
R
Caraballo
Department of Medical Biosciences, Umeå University, SE-901 87 Umeå, Sweden.
Mikael
M
Larsson
Department of Medical Biosciences, Umeå University, SE-901 87 Umeå, Sweden.
Stefan K
SK
Nilsson
Department of Medical Biosciences, Umeå University, SE-901 87 Umeå, Sweden.
Madelene
M
Ericsson
Laboratories for Chemical Biology Umeå, Chemical Biology Consortium Sweden, Umeå University, SE-901 87 Umeå, Sweden.
Weixing
W
Qian
Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
Nam Phuong
NP
Nguyen Tran
Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
Tomas
T
Kindahl
Department of Pharmacy, Uppsala University, Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium Sweden, Science for Life Laboratory Uppsala, SE-751 23 Uppsala, Sweden.
Richard
R
Svensson
Department of Medical Biosciences, Umeå University, SE-901 87 Umeå, Sweden.
Valeria
V
Saar
Department of Pharmacy, Uppsala University, Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium Sweden, Science for Life Laboratory Uppsala, SE-751 23 Uppsala, Sweden.
Per
P
Artursson
Department of Medical Biosciences, Umeå University, SE-901 87 Umeå, Sweden.
Gunilla
G
Olivecrona
Laboratories for Chemical Biology Umeå, Chemical Biology Consortium Sweden, Umeå University, SE-901 87 Umeå, Sweden.
Per-Anders
PA
Enquist
Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden; Laboratories for Chemical Biology Umeå, Chemical Biology Consortium Sweden, Umeå University, SE-901 87 Umeå, Sweden. Electronic address: mikael.elofsson@umu.se.
Mikael
M
Elofsson
D000818:Animals; D018938:Caco-2 Cells; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D057166:High-Throughput Screening Assays; D006801:Humans; D008071:Lipoprotein Lipase / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D010797:Phthalimides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood*
D010797:Phthalimides; D014280:Triglycerides; C037430:N-phenylphthalimide; D008071:Lipoprotein Lipase
Agonist; LPL; Lipoprotein lipase; Structure–activity relationship; Triglyceride