Bioorg Med Chem Lett. 2006 Nov 1;16(21):5488-92. Epub 2006 Aug 22.

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

Epple R, Azimioara M, Russo R, Xie Y, Wang X, Cow C, Wityak J, Karanewsky D, Bursulaya B, Kreusch A, Tuntland T, Gerken A, Iskandar M, Saez E, Martin Seidel H, Tian SS.

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Department of Medicinal Chemistry, The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA. repple@gnf.org

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.

PMID:: 16931011; [PubMed - indexed for MEDLINE]

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Adaptability and selectivity of human peroxisome proliferator-activated receptor (PPAR) pan agonists revealed from crystal structures.
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Structures reported by this article

3,4,5-Trisubstituted Isoxazoles As Novel Ppardelta Agonists: Part2

PDB: 2J14

Source: Homo sapiens

Method: X-Ray Diffraction

Resolution: 2.8 Å

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