Large dimeric ligands with favorable pharmacokinetic properties and peroxisome proliferator-activated receptor agonist activity in vitro and in vivo.
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.
Per Sauerberg, Novo Nordisk A/S, Novo Nordisk Park, 2760 Måløv, Denmark. psa@novonordisk.com
Per
P
Sauerberg
Paul S
PS
Bury
John P
JP
Mogensen
Heinz-Josef
HJ
Deussen
Ingrid
I
Pettersson
Jan
J
Fleckner
Jan
J
Nehlin
Klaus S
KS
Frederiksen
Tatjana
T
Albrektsen
Nanni
N
Din
L Anders
LA
Svensson
Lars
L
Ynddal
Erik M
EM
Wulff
Lone
L
Jeppesen
D000475:Alkenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D002460:Cell Line; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011422:Propionates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D013237:Stereoisomerism; D014157:Transcription Factors / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D015533:Transcriptional Activation
D000475:Alkenes; D008024:Ligands; D011422:Propionates; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors