Synthesis and biological activity of L-tyrosine-based PPARgamma agonists with reduced molecular weight

K G Liu; M H Lambert; A H Ayscue; B R Henke; L M Leesnitzer; W R Oliver Jr; K D Plunket; H E Xu; D D Sternbach; T M Willson

doi:10.1016/s0960-894x(01)00649-7

Synthesis and biological activity of L-tyrosine-based PPARgamma agonists with reduced molecular weight

Bioorg Med Chem Lett. 2001 Dec 17;11(24):3111-3. doi: 10.1016/s0960-894x(01)00649-7.

Authors

K G Liu¹, M H Lambert, A H Ayscue, B R Henke, L M Leesnitzer, W R Oliver Jr, K D Plunket, H E Xu, D D Sternbach, T M Willson

Affiliation

¹ Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. kliu@kalypsys.com

PMID: 11720854
DOI: 10.1016/s0960-894x(01)00649-7

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.

MeSH terms

Animals
Diabetes Mellitus, Experimental / drug therapy
Hypoglycemic Agents / chemical synthesis*
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacology*
Hypoglycemic Agents / therapeutic use
Male
Molecular Weight
Rats
Rats, Zucker
Receptors, Cytoplasmic and Nuclear / agonists*
Transcription Factors / agonists*
Tyrosine / chemical synthesis*

Substances

Hypoglycemic Agents
Receptors, Cytoplasmic and Nuclear
Transcription Factors
Tyrosine