Novel tricyclic-alpha-alkyloxyphenylpropionic acids: dual PPARalpha/gamma agonists with hypolipidemic and antidiabetic activity.
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.
Sauerberg
Per
P
Novo Nordisk A/S, Novo Nordisk Park E9 2.02, 2760 Måløv, Denmark. psa@novonordisk.com
Pettersson
Ingrid
I
Jeppesen
Lone
L
Bury
Paul S
PS
Mogensen
John P
JP
Wassermann
Karsten
K
Brand
Christian L
CL
Sturis
Jeppe
J
Wöldike
Helle F
HF
Fleckner
Jan
J
Andersen
Anne-Sofie T
AS
Mortensen
Steen B
SB
Svensson
L Anders
LA
Rasmussen
Hanne B
HB
Lehmann
Søren V
SV
Polivka
Zdenek
Z
Sindelar
Karel
K
Panajotova
Vladimira
V
Ynddal
Lars
L
Wulff
Erik M
EM
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000819:agonists*; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D000077154:Rosiglitazone; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists*; D014280:Triglycerides / Q000097:blood
C448626:3-(4-(2-carbazol-9-ylethoxy)phenyl)-2-ethoxypropionic acid; D001786:Blood Glucose; D002227:Carbazoles; D002791:Cholesterol, Dietary; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D009687:Nuclear Proteins; D010666:Phenylpropionates; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014280:Triglycerides; D000077154:Rosiglitazone; D002784:Cholesterol; D000077205:Pioglitazone