Design, synthesis, and structure-activity relationship studies of novel 6,7-locked-[7-(2-alkoxy-3,5-dialkylbenzene)-3-methylocta]-2,4,6-trienoic acids

  • J Med Chem. 2003 Sep 11;46(19):4087-103. doi: 10.1021/jm020401k.
Pierre-Yves Michellys  1 ,  Robert J Ardecky ,  Jyun-Hung Chen ,  Jennifer D'Arrigo ,  Timothy A Grese ,  Donald S Karanewsky ,  Mark D Leibowitz ,  Sha Liu ,  Dale A Mais ,  Christopher M Mapes ,  Chahrzad Montrose-Rafizadeh ,  Katheen M Ogilvie ,  Anne Reifel-Miller ,  Deepa Rungta ,  Anthony W Thompson ,  John S Tyhonas ,  Marcus F Boehm
Affiliations
  • 1. Department of Medicinal Chemistry, Ligand Pharmaceuticals, Inc., 10275 Science Center Drive, San Diego, California 92121, USA. [email protected]
PMID: 12954061 DOI: 10.1021/jm020401k
Abstract

Retinoid X receptor:peroxisome proliferative-activated receptor (RXR:PPAR) heterodimers play a critical role in the regulation of glucose (RXR/PPARgamma) and lipid metabolism (RXR/PPARalpha). Previously, we described a concise structure-activity relationship study of selective RXR modulators possessing a (2E,4E,6Z)-3-methyl-7-(3,5-dialkyl-6-alkoxyphenyl)-octa-2,4,6-trienoic acid scaffold. These studies were focused on the 2-position alkoxy side chain. We describe here the design and synthesis of a novel series of RXR selective modulators possessing the same aromatic core structure with the addition of a ring locked 6-7-Z-olefin on the trienoic acid moiety. The synthesis and structure-activity relationship studies of these 6,7-locked cyclopentenyl, phenyl, thienyl, furan, and pyridine-trienoic acid derivatives is presented herein.