title: Novel tricyclic-alpha-alkyloxyphenylpropionic acids: dual PPARalpha/gamma agonists with hypolipidemic and antidiabetic activity.
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.
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park E9 2.02, 2760 Måløv, Denmark. psa@novonordisk.com
authors.forename: Per
authors.initials: P
authors.lastname: Sauerberg
authors.forename: Ingrid
authors.initials: I
authors.lastname: Pettersson
authors.forename: Lone
authors.initials: L
authors.lastname: Jeppesen
authors.forename: Paul S
authors.initials: PS
authors.lastname: Bury
authors.forename: John P
authors.initials: JP
authors.lastname: Mogensen
authors.forename: Karsten
authors.initials: K
authors.lastname: Wassermann
authors.forename: Christian L
authors.initials: CL
authors.lastname: Brand
authors.forename: Jeppe
authors.initials: J
authors.lastname: Sturis
authors.forename: Helle F
authors.initials: HF
authors.lastname: Wöldike
authors.forename: Jan
authors.initials: J
authors.lastname: Fleckner
authors.forename: Anne-Sofie T
authors.initials: AS
authors.lastname: Andersen
authors.forename: Steen B
authors.initials: SB
authors.lastname: Mortensen
authors.forename: L Anders
authors.initials: LA
authors.lastname: Svensson
authors.forename: Hanne B
authors.initials: HB
authors.lastname: Rasmussen
authors.forename: Søren V
authors.initials: SV
authors.lastname: Lehmann
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Polivka
authors.forename: Karel
authors.initials: K
authors.lastname: Sindelar
authors.forename: Vladimira
authors.initials: V
authors.lastname: Panajotova
authors.forename: Lars
authors.initials: L
authors.lastname: Ynddal
authors.forename: Erik M
authors.initials: EM
authors.lastname: Wulff
mesh_terms: 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
chemical_list: 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