Novel tricyclic-alpha-alkyloxyphenylpropionic acids: dual PPARalpha/gamma agonists with hypolipidemic and antidiabetic activity.

Article Details

Citation

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
DrugTargetPropertyMeasurementpHTemperature (°C)
(2S)-2-ETHOXY-3-{4-[2-(10H-PHENOXAZIN-10-YL)ETHOXY]PHENYL}PROPANOIC ACIDPeroxisome proliferator-activated receptor gammaEC 50 (nM)570N/AN/ADetails
(S)-3-(4-(2-Carbazol-9-Yl-Ethoxy)-Phenyl)-2-Ethoxy-Propionic AcidPeroxisome proliferator-activated receptor gammaEC 50 (nM)170N/AN/ADetails
BezafibratePeroxisome proliferator-activated receptor alphaEC 50 (nM)35700N/AN/ADetails
BezafibratePeroxisome proliferator-activated receptor deltaEC 50 (nM)102000N/AN/ADetails
BezafibratePeroxisome proliferator-activated receptor gammaEC 50 (nM)73500N/AN/ADetails
PioglitazonePeroxisome proliferator-activated receptor gammaEC 50 (nM)970N/AN/ADetails
RosiglitazonePeroxisome proliferator-activated receptor alphaEC 50 (nM)4100N/AN/ADetails
RosiglitazonePeroxisome proliferator-activated receptor gammaEC 50 (nM)160N/AN/ADetails
TroglitazonePeroxisome proliferator-activated receptor gammaEC 50 (nM)980N/AN/ADetails