3,4,5-Trisubstituted isoxazoles as novel PPARdelta agonists. Part 2

  • Bioorg Med Chem Lett. 2006 Nov 1;16(21):5488-92. doi: 10.1016/j.bmcl.2006.08.052.
Robert Epple  1 ,  Mihai Azimioara ,  Ross Russo ,  Yongping Xie ,  Xing Wang ,  Christopher Cow ,  John Wityak ,  Don Karanewsky ,  Badry Bursulaya ,  Andreas Kreusch ,  Tove Tuntland ,  Andrea Gerken ,  Maya Iskandar ,  Enrique Saez ,  H Martin Seidel ,  Shin-Shay Tian
Affiliations
  • 1. Department of Medicinal Chemistry, The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA. [email protected]
PMID: 16931011 DOI: 10.1016/j.bmcl.2006.08.052
Abstract

A series of PPARdelta-selective agonists was investigated and optimized for a favorable in vivo pharmacokinetic profile. Isoxazole LCI765 (17d) was found to be a potent and selective PPARdelta agonist with good in vivo PK properties in mouse (C(max)=5.1 microM, t(1/2)=3.1 h). LCI765 regulated expression of genes involved in energy homeostasis in relevant tissues when dosed orally in C57BL6 mice. A co-crystal structure of compound LCI765 and the LBD of PPARdelta is discussed.

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