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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
Bioorg Med Chem Lett 16 5488-92 (2006)
Cited: 19 times
EuropePMC logo PMID: 16931011

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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  3. Knowledge-Based Methods To Train and Optimize Virtual Screening Ensembles. Swift RV, Jusoh SA, Offutt TL, Li ES, Amaro RE. J Chem Inf Model 56 830-842 (2016)
  4. Identified the Synergistic Mechanism of Drynariae Rhizoma for Treating Fracture Based on Network Pharmacology. Lin H, Wang X, Wang L, Dong H, Huang P, Cai Q, Mo Y, Huang F, Jiang Z. Evid Based Complement Alternat Med 2019 7342635 (2019)
  5. Identification and Molecular Characterization of Peroxisome Proliferator-Activated Receptor δ as a Novel Target for Covalent Modification by 15-Deoxy-Δ12,14-prostaglandin J2. Reddy AT, Lakshmi SP, Banno A, Reddy RC. ACS Chem Biol 13 3269-3278 (2018)


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  1. Role of Pleiotropic Properties of Peroxisome Proliferator-Activated Receptors in the Heart: Focus on the Nonmetabolic Effects in Cardiac Protection. Barlaka E, Galatou E, Mellidis K, Ravingerova T, Lazou A. Cardiovasc Ther 34 37-48 (2016)
  2. Structural Biology-Based Exploration of Subtype-Selective Agonists for Peroxisome Proliferator-Activated Receptors. Miyachi H. Int J Mol Sci 22 9223 (2021)

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  1. Structural basis for specific ligation of the peroxisome proliferator-activated receptor δ. Wu CC, Baiga TJ, Downes M, La Clair JJ, Atkins AR, Richard SB, Fan W, Stockley-Noel TA, Bowman ME, Noel JP, Evans RM. Proc Natl Acad Sci U S A 114 E2563-E2570 (2017)
  2. Design, synthesis, and evaluation of potent, structurally novel peroxisome proliferator-activated receptor (PPAR) delta-selective agonists. Kasuga J, Nakagome I, Aoyama A, Sako K, Ishizawa M, Ogura M, Makishima M, Hirono S, Hashimoto Y, Miyachi H. Bioorg Med Chem 15 5177-5190 (2007)
  3. Structure-based virtual screening and discovery of New PPARδ/γ dual agonist and PPARδ and γ agonists. Maltarollo VG, Togashi M, Nascimento AS, Honorio KM. PLoS One 10 e0118790 (2015)
  4. Discovery of isoindoline and tetrahydroisoquinoline derivatives as potent, selective PPARδ agonists. Luckhurst CA, Stein LA, Furber M, Webb N, Ratcliffe MJ, Allenby G, Botterell S, Tomlinson W, Martin B, Walding A. Bioorg Med Chem Lett 21 492-496 (2011)
  5. Anthranilic acid derivatives as nuclear receptor modulators--development of novel PPAR selective and dual PPAR/FXR ligands. Merk D, Lamers C, Weber J, Flesch D, Gabler M, Proschak E, Schubert-Zsilavecz M. Bioorg Med Chem 23 499-514 (2015)
  6. Determination of the critical amino acids involved in the peroxisome proliferator-activated receptor (PPAR) delta selectivity of phenylpropanoic acid-derived agonists. Kasuga J, Oyama T, Nakagome I, Makishima M, Hirono S, Morikawa K, Hashimoto Y, Miyachi H. ChemMedChem 3 1662-1666 (2008)
  7. Discovery of para-alkylthiophenoxyacetic acids as a novel series of potent and selective PPARdelta agonists. Zhang R, Wang A, DeAngelis A, Pelton P, Xu J, Zhu P, Zhou L, Demarest K, Murray WV, Kuo GH. Bioorg Med Chem Lett 17 3855-3859 (2007)
  8. 3-(Arylthiomethyl)isoxazole-4,5-dicarboxamides: chemoselective nucleophilic chemistry and insecticidal activity. Yu GJ, Iwamoto S, Robins LI, Fettinger JC, Sparks TC, Lorsbach BA, Kurth MJ. J Agric Food Chem 57 7422-7426 (2009)
  9. Synthesis and biological evaluation of N-alkylated 8-oxybenz[c]azepine derivatives as selective PPARδ agonists. Luckhurst CA, Ratcliffe M, Stein L, Furber M, Botterell S, Laughton D, Tomlinson W, Weaver R, Chohan K, Walding A. Bioorg Med Chem Lett 21 531-536 (2011)
  10. Novel selective PPARdelta agonists: optimization of activity by modification of alkynylallylic moiety. Havranek M, Sauerberg P, Mogensen JP, Kratina P, Jeppesen CB, Pettersson I, Pihera P. Bioorg Med Chem Lett 17 4144-4149 (2007)
  11. Structural Development Studies of Subtype-Selective Ligands for Peroxisome Proliferator-Activated Receptors (PPARs) Based on the 3,4-Disubstituted Phenylpropanoic Acid Scaffold as a Versatile Template. Miyachi H, Hashimoto Y. PPAR Res 2008 689859 (2008)
  12. Synthesis of 2-Oxo-1, 2-Dihydroquinoline Chemotype with Multiple Attachment Points as Novel Screening Compounds for Drug Discovery. Kurkin AV, Altieri A, Andreev IA, Debnath AK. JSM Chem 4 1033 (2016)


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