3. Barish, G. D.; Narkar, V. A,; Evans, R. M. J Clin Invest 2006, 116, 590.
4. Fan, W.; Waizenegger, W.; Lin, C. S.;Sorrentino,V.; He, M.; Wall, C. E.; Li, H.; Christopher Liddle,
C.; Yu, R. T.; Atkins, A. R.; Auwerx, J.; Downes,M.;Evans, R. M. Cell Metabolism 2017, 25, 1186.
5. Wu, C.-C.; Baiga, T. J.; Downes, M.; La Clair, J. J.; Atkins, A. R.; Richard, S. B.; Fan, W.; Stockley-
Noel, T. A.; Bowman, M. E.; Noel, J. P.; Evans, R. M. Proc. Natl. Acad. Sci. 2017, 114, E2563.
6. Oliver, Jr., W. R.; Shenk, J. L.; Snaith, M. R.; Russell, C. S.; Plunket, K. D.; Bodkin, N. L.; Lewis, M.
C.; Winegar; D. A.; Sznaidman, M. L.; Lambert, M. H.; Xu, H. E.; Sternbach, D. D.; Kliewer, S. A.;
Hansen, B. C.; Willson, T.M. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 5306.
7. The maximum rate for clearance/extinction of a drug given i.v. to a mouse is the cardiac output (CO),
which is approximately 500 mL/min/kg: see Janssen, B.; Debets, J.; Leenders, P.; Smits, J. Amer. J.
Physiol. 2002, 282, R928.
8. In this letter plasma clearance (CL) is categorized as high, medium or low with respect to its
percentage of total CO. Clearance is ranked as high if it is above 0.35 CO, medium if it is around 0.15
CO and low if it is around 0.05 CO: see Toutain, P. L.;Bousquet-Melou, A. J. Vet. Pharmacol. Therap.
2004, 27, 415.
9. Detailed synthetic schemes and procedures for preparing the compounds described in this letter can be
found in PCT Int. Appl. WO 2016057660..
10. Davies, B.; Morris, T, Pharmaceutical Res. 1993, 10, 1093
11. All the animal experiments were carried out as per the guidelines of the Committee for the Purpose of
Control and Supervision of Experiments on Animals (CPCSEA), Government of India and approved
by the Institutional Animal Ethics Committee (IAEC), Aurigene Discovery Technologies Ltd,
Bengaluru, India.
12. Compound (10 mmol/L) was incubated with cryopreserved rat (male and female) and human (gender
mixed) hepatocytes (1 X 106 cells/mL) at 37⁰C in for 30 and 120 min. The metabolites were analyzed
by LC-MS. The authors thank Dr. Keitarou Kadono (Astellas Pharma) for the data.
13. Compounds were dosed as a solution in 2% DMA , 20% HPβCD intravenously.at 3 mg/kg to male
CD-1 mice. A standard elimination curve was generated by measuring plasma exposure at 10 points
between 0-24h. The values shown are an average of three determinations at each time point.
14.
15. In the protein interaction assay the PPAR ligand complexes with a PPAR ligand binding domain fused
to an inactive fragment of galactosidase. This complex complements another inactive galactosidase
fragment to form an active galactosidase enzyme that is read out in a fluorescence assay. See
modulators of PPARα and PPARγ. Compound 1, with a mean EC50 of 9.8 2.5 nM, served as a
positive control for PPARδ in each run.
16. In the transactivation assay CV-1 cells are transfected with a PPAR ligand binding domain fused to a
GAL4 promoter to generate a hormone-inducible activator. A test ligand is added and activity is
measured in a luciferase assay. See WO2016057660 for further details.
17. SPR binding studies were performed with PPARδ His-tagged (33.2 kD)at 25ºC using a one-shot
kinetics approach. BioRad ProteOn XPR36 optical biosensor equipped with a nickel-charged, NTA-
derivatized GLH sensor chip and equilibrated with running buffer (10 mM HEPES, 150 mM NaCl, 5%
glycerol, 1 mM TCEP, 0.005% Tween-20, pH 7.5) was used for analysis.
18. Coordinates of the X-ray structure have been deposited in the Protein Data Bank (accession code PDB
5XMX). The residue numbering follows the UniProt residue numbering convention in accession
number Q03181 (PPARD_HUMAN).
19. Lagu, B.; Kluge, A. F.; Goddeeris, M. M.; Tozzo, E.; Fredenburg, R. A.; Chellur, S.; Senaiar, R. S.;
Jaleel, M.; Babu, D. R. K.; Tiwari, N. K.; Takahashi, T.; Patane, M. A. Bioorg. Med. Chem. Lett. 2017
(accompanying paper).
Graphical Abstract
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