European Journal of Medicinal Chemistry p. 191 - 209 (2015)
Update date:2022-08-15
Topics:
Caraballo, Rémi
Larsson, Mikael
Nilsson, Stefan K.
Ericsson, Madelene
Qian, Weixing
Tran, Nam Phuong Nguyen
Kindahl, Tomas
Svensson, Richard
Saar, Valeria
Artursson, Per
Olivecrona, Gunilla
Enquist, Per-Anders
Elofsson, Mikael
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.
View MoreAnhui Gusheng Import&Export CO.,LTD
Contact:86-551-63662296
Address:Jinzhai Road NO.162 ,hefei, china
Dalian Synco Chemical Co., Ltd.
Contact:+86-411-83635150
Address:Rm 1004, 24, Tangshan Street, Dalian
website:http://www.tbbmed.com
Contact:86--21-50498136
Address:Room 6002, Building 7-1, No.160 Basheng Road,Pudong Area,Shanghai China
Hangzhou Taiyan Trading Co., Ltd(expird)
Contact:+86-13777583958
Address:NO.63, Xingyi Street, Xihu District, Hangzhou, Zhejiang, China
Contact:+86-710-3516804
Address:Number 83,Panggong road,Xiangcheng District,Xiangyang ,Hubei
Doi:10.1080/10587250108025060
(2001)Doi:10.3390/molecules26154446
(2021)Doi:10.1007/BF00476809
()Doi:10.1021/jo00982a042
(1972)Doi:10.1021/ja01112a532
(1953)Doi:10.1039/b009448j
(2001)