Amphipathic 3-phenyl-7-propylbenzisoxazoles; human PPaR γ, δ and α agonists

Bioorganic and Medicinal Chemistry Letters

Volumn 13, Issue 5, 2003, Pages 931-935

  Adams, Alan D ^a   Yuen, Winston ^a   Hu, Zao ^a   Santini, Conrad ^a   Jones, A Brian ^a   MacNaul, Karen L ^a   Berger, Joel P ^a   Doebber, Thomas W ^a   Moller, David E ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ISOXAZOLE DERIVATIVE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA AGONIST; ROSIGLITAZONE; UNCLASSIFIED DRUG;

ARTICLE; CONTROLLED STUDY; DRUG EFFICACY; HUMAN; HYPERGLYCINEMIA; HYPERTRIGLYCERIDEMIA; IN VITRO STUDY; IN VIVO STUDY; MODEL; MOUSE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN;

EID: 0037430564     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(02)01029-6     Document Type: Article

References (28)

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13. i.
14. 1H NMR spectra and satisfactory LCMS data.
15. i ratios using the van't Hoff reaction isotherm.
16. i 7.2 nM, Stdev 2.7.
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20. The carboxy residue present in all agonists reported here is required for agonist activity. For example, the nitriles corresponding to 6 and 15 show no titratable affinity for any of the receptors. The carboxy proximal fragment is not, however, sufficient for measurable affinity. Phenyl acetic acid, 3-phenylpropionic acid and clofibric acid also show no measurable affinity for any of the receptors. Exactly this paradox of attribution and additivity of binding energy is discussed in Jencks W.P. Proc. Natl. Acad. Sci. USA. 78:1981;4046.
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22. Pharmacokinetics were evaluated in male Sprague Dawley rats with 0.5 mpk iv and 2.0 mpk po doses.
23. Pivichny et al. Unpublished.
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25. See refs 118-120 in Willson et al. (ref 1) Many studies show improvement of glucose homeostasis using Bezafibrate in humans; Smud R., Sermukslis B. Curr. Med. Res. Opinion. 10:1987;612 Mikhailidis D., Mathur S., Barradas M.A., Dandona P. J Cardiovasc Pharm. 16:1990;S26 Durrington P.N., Winocour P.H., Bhatnagar D. J. Cardiovasc. Pharmacol. 16:1990;S30 Attia N., Durlach V., Roche D., Paul J.L., Soni T., Zahouani A., Landron F., Labrousse F., Leutenegger M., Girard-Globa A. Eur. J. Clin. Invest. 27:1997;55.
26. See refs 118-120 in Willson et al. (ref 1) Many studies show improvement of glucose homeostasis using Bezafibrate in humans; Smud R., Sermukslis B. Curr. Med. Res. Opinion. 10:1987;612 Mikhailidis D., Mathur S., Barradas M.A., Dandona P. J Cardiovasc Pharm. 16:1990;S26 Durrington P.N., Winocour P.H., Bhatnagar D. J. Cardiovasc. Pharmacol. 16:1990;S30 Attia N., Durlach V., Roche D., Paul J.L., Soni T., Zahouani A., Landron F., Labrousse F., Leutenegger M., Girard-Globa A. Eur. J. Clin. Invest. 27:1997;55.
27. See refs 118-120 in Willson et al. (ref 1) Many studies show improvement of glucose homeostasis using Bezafibrate in humans; Smud R., Sermukslis B. Curr. Med. Res. Opinion. 10:1987;612 Mikhailidis D., Mathur S., Barradas M.A., Dandona P. J Cardiovasc Pharm. 16:1990;S26 Durrington P.N., Winocour P.H., Bhatnagar D. J. Cardiovasc. Pharmacol. 16:1990;S30 Attia N., Durlach V., Roche D., Paul J.L., Soni T., Zahouani A., Landron F., Labrousse F., Leutenegger M., Girard-Globa A. Eur. J. Clin. Invest. 27:1997;55.
28. See refs 118-120 in Willson et al. (ref 1) Many studies show improvement of glucose homeostasis using Bezafibrate in humans; Smud R., Sermukslis B. Curr. Med. Res. Opinion. 10:1987;612 Mikhailidis D., Mathur S., Barradas M.A., Dandona P. J Cardiovasc Pharm. 16:1990;S26 Durrington P.N., Winocour P.H., Bhatnagar D. J. Cardiovasc. Pharmacol. 16:1990;S30 Attia N., Durlach V., Roche D., Paul J.L., Soni T., Zahouani A., Landron F., Labrousse F., Leutenegger M., Girard-Globa A. Eur. J. Clin. Invest. 27:1997;55.