title: Synthesis and biological activity of L-tyrosine-based PPARgamma agonists with reduced molecular weight.
abstract: 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.
authors.affiliation: Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. kliu@kalypsys.com
authors.forename: K G
authors.initials: KG
authors.lastname: Liu
authors.forename: M H
authors.initials: MH
authors.lastname: Lambert
authors.forename: A H
authors.initials: AH
authors.lastname: Ayscue
authors.forename: B R
authors.initials: BR
authors.lastname: Henke
authors.forename: L M
authors.initials: LM
authors.lastname: Leesnitzer
authors.forename: W R
authors.initials: WR
authors.lastname: Oliver
authors.forename: K D
authors.initials: KD
authors.lastname: Plunket
authors.forename: H E
authors.initials: HE
authors.lastname: Xu
authors.forename: D D
authors.initials: DD
authors.lastname: Sternbach
authors.forename: T M
authors.initials: TM
authors.lastname: Willson
mesh_terms: 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*
chemical_list: D007004:Hypoglycemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014443:Tyrosine