Design and synthesis of novel and potent amide linked PPARgamma/delta dual agonists

Qing Shi; Emily J Canada; Yanping Xu; Alan M Warshawsky; Garret J Etgen; Carol L Broderick; Cathleen K Clutinger; Lynnie A Irwin; Michael E Laurila; Chahrzad Montrose-Rafizadeh; Brian A Oldham; Minmin Wang; Leonard L Winneroski; Chaoyu Xie; Jeremy S York; Nathan P Yumibe; Richard W Zink; Nathan Mantlo

doi:10.1016/j.bmcl.2007.10.047

Design and synthesis of novel and potent amide linked PPARgamma/delta dual agonists

Bioorg Med Chem Lett. 2007 Dec 15;17(24):6744-9. doi: 10.1016/j.bmcl.2007.10.047. Epub 2007 Oct 18.

Authors

Qing Shi¹, Emily J Canada, Yanping Xu, Alan M Warshawsky, Garret J Etgen, Carol L Broderick, Cathleen K Clutinger, Lynnie A Irwin, Michael E Laurila, Chahrzad Montrose-Rafizadeh, Brian A Oldham, Minmin Wang, Leonard L Winneroski, Chaoyu Xie, Jeremy S York, Nathan P Yumibe, Richard W Zink, Nathan Mantlo

Affiliation

¹ Eli Lilly and Company, Lilly Research Labs, Lilly Corporate Center, Indianapolis, IN 46285, USA. shi_qing@lilly.com

PMID: 18029178
DOI: 10.1016/j.bmcl.2007.10.047

Abstract

A series of potent amide linked PPARgamma/delta dual agonists (1a) has been discovered through rational design. In the ZDF rat model of type 2 diabetes, compound (R)-3-[4-(3-{1-[(5-chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid (42) from this series has demonstrated glucose lowering efficacy comparable to the marketed PPARgamma agonist rosiglitazone with less weight gain.

MeSH terms

Amides / chemistry*
Animals
Combinatorial Chemistry Techniques
Diabetes Mellitus, Type 2 / drug therapy
Disease Models, Animal
Drug Design*
Indoles / chemical synthesis*
Indoles / chemistry
Indoles / pharmacology
Molecular Structure
PPAR delta / agonists*
PPAR gamma / agonists*
Rats

Substances

(R)-3-(4-(3-(1-((5-chloro-1,3-dimethyl-1H-indole-2-carbonyl)amino)ethyl)-5-fluoro-phenoxy)-2-ethylphenyl)propionic acid
Amides
Indoles
PPAR delta
PPAR gamma