Design, synthesis, and biological activity of novel PPARgamma ligands based on rosiglitazone and 15d-PGJ2.
To develop novel PPARgamma ligands, we synthesized thirteen 3-{4-(2-aminoethoxy)phenyl}propanoic acid derivatives, which are designed based on the structures of rosiglitazone and 15d-PGJ2. Among these compounds, compound 9 was found to be as potent as rosiglitazone in a binding assay and a preadipocyte differentiation test. Molecular modeling suggested that the nonyl group of 9 interacted with hydrophobic amino acid residues constructing the hydrophobic region of PPARgamma protein where the alkyl chain of 15d-PGJ2 is expected to be located.
Usui
Shinya
S
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
Suzuki
Takayoshi
T
Hattori
Yoshifumi
Y
Etoh
Kazuma
K
Fujieda
Hiroki
H
Nishizuka
Makoto
M
Imagawa
Masayoshi
M
Nakagawa
Hidehiko
H
Kohda
Kohfuku
K
Miyata
Naoki
N
D017667:Adipocytes / Q000187:drug effects; D000818:Animals; D002478:Cells, Cultured; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D047495:PPAR gamma / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000737:chemistry*; D011485:Protein Binding; D051381:Rats; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000737:chemistry*
C477819:15-deoxyprostaglandin J2; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D015230:Prostaglandin D2