Novel tricyclic-alpha-alkyloxyphenylpropionic acids: dual PPARalpha/gamma agonists with hypolipidemic and antidiabetic activity.
Article Details
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Sauerberg P, Pettersson I, Jeppesen L, Bury PS, Mogensen JP, Wassermann K, Brand CL, Sturis J, Woldike HF, Fleckner J, Andersen AS, Mortensen SB, Svensson LA, Rasmussen HB, Lehmann SV, Polivka Z, Sindelar K, Panajotova V, Ynddal L, Wulff EM
Novel tricyclic-alpha-alkyloxyphenylpropionic acids: dual PPARalpha/gamma agonists with hypolipidemic and antidiabetic activity.
J Med Chem. 2002 Feb 14;45(4):789-804.
- PubMed ID
- 11831892 [ View in PubMed]
- Abstract
Synthesis and structure-activity relationships of tricyclic alpha-ethoxy-phenylpropionic acid derivatives guided by in vitro PPARalpha and PPARgamma transactivation data and computer modeling led to the identification of the novel carbazole analogue, 3q, with dual PPARalpha (EC(50) = 0.36 microM) and PPARgamma (EC(50) = 0.17 microM) activity in vitro. Ten days treatment of db/db mice with 3q improved the insulin sensitivity, as measured by OGTT, better than that seen with both pioglitazone and rosiglitazone treatment, suggesting in vivo PPARgamma activity. Likewise, 3q lowered plasma triglycerides and cholesterol in high cholesterol fed rats after 4 days treatment, indicating in vivo PPARalpha activity. Investigations of the pharmacokinetics of selected compounds suggested that extended drug exposure improved the in vivo activity of in vitro active compounds.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) (2S)-2-ETHOXY-3-{4-[2-(10H-PHENOXAZIN-10-YL)ETHOXY]PHENYL}PROPANOIC ACID Peroxisome proliferator-activated receptor gamma EC 50 (nM) 570 N/A N/A Details (S)-3-(4-(2-Carbazol-9-Yl-Ethoxy)-Phenyl)-2-Ethoxy-Propionic Acid Peroxisome proliferator-activated receptor gamma EC 50 (nM) 170 N/A N/A Details Bezafibrate Peroxisome proliferator-activated receptor alpha EC 50 (nM) 35700 N/A N/A Details Bezafibrate Peroxisome proliferator-activated receptor delta EC 50 (nM) 102000 N/A N/A Details Bezafibrate Peroxisome proliferator-activated receptor gamma EC 50 (nM) 73500 N/A N/A Details Pioglitazone Peroxisome proliferator-activated receptor gamma EC 50 (nM) 970 N/A N/A Details Rosiglitazone Peroxisome proliferator-activated receptor alpha EC 50 (nM) 4100 N/A N/A Details Rosiglitazone Peroxisome proliferator-activated receptor gamma EC 50 (nM) 160 N/A N/A Details Troglitazone Peroxisome proliferator-activated receptor gamma EC 50 (nM) 980 N/A N/A Details