Large dimeric ligands with favorable pharmacokinetic properties and peroxisome proliferator-activated receptor agonist activity in vitro and in vivo.

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Sauerberg P, Bury PS, Mogensen JP, Deussen HJ, Pettersson I, Fleckner J, Nehlin J, Frederiksen KS, Albrektsen T, Din N, Svensson LA, Ynddal L, Wulff EM, Jeppesen L

Large dimeric ligands with favorable pharmacokinetic properties and peroxisome proliferator-activated receptor agonist activity in vitro and in vivo.

J Med Chem. 2003 Nov 6;46(23):4883-94.

PubMed ID

14584939 [ View in PubMed

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Abstract

Two potent nonselective, but PPARalpha-preferring, PPAR agonists 5 and 6 were designed and synthesized in high yields. The concept of dimeric ligands in transcription factors was investigated by synthesizing and testing the corresponding dimers 7, 8a, and 8b in PPAR transactivation assays. The three dimeric ligands all showed agonist activity on all three PPAR receptor subtypes, but with different profiles compared to the monomers 5 and 6. Despite breaking all the "rule of five" criteria, the dimers had excellent oral bioavailability and pharmacokinetic properties, resulting in good in vivo efficacy in db/db mice. X-ray crystal structure and modeling experiments suggested that the dimers interacted with the AF-2 helix as well as with amino acid residues in the lipophilic pocket close to the receptor surface.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
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