Synthesis and biological activity of L-tyrosine-based PPARgamma agonists with reduced molecular weight.
A series of PPARgamma agonists were synthesized from L-tyrosine that incorporated low molecular weight N-substituents. The most potent analogue, pyrrole (4e), demonstrated a K(i) of 6.9nM and an EC(50) of 4.7nM in PPARgamma binding and functional assays, respectively. Pyrrole (4e), which is readily synthesized from L-tyrosine methyl ester in four steps, also demonstrated in vivo activity in a rodent model of Type 2 diabetes.
Liu
K G
KG
Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. kliu@kalypsys.com
Lambert
M H
MH
Ayscue
A H
AH
Henke
B R
BR
Leesnitzer
L M
LM
Oliver
W R
WR
Plunket
K D
KD
Xu
H E
HE
Sternbach
D D
DD
Willson
T M
TM
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008970:Molecular Weight; D051381:Rats; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D014157:Transcription Factors / Q000819:agonists*; D014443:Tyrosine / Q000138:chemical synthesis*
D007004:Hypoglycemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014443:Tyrosine