N-(2-benzoylphenyl)-L-tyrosine PPARγ agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents

Brad R. Henke, Steven G. Blanchard, Marcus F. Brackeen, Kathleen K. Brown, Jeff E. Cobb, Jon L. Collins, W. Wallace Harrington, Mir A. Hashim, Emily A. Hull-Ryde, Istvan Kaldor, Steven A. Kliewer, Debra H. Lake, Lisa M. Leesnitzer, Jürgen M. Lehmann, James M. Lenhard, Lisa A. Orband-Miller, John F. Miller, Robert A. Mook, Stewart A. Noble, William OliverDerek J. Parks, Kelli D. Plunket, Jerzy R. Szewczyk, Timothy M. Willson

Research output: Contribution to journalArticle

278 Scopus citations

Abstract

We have identified a novel series of antidiabetic N-(2-benzoylphenyl)- L-tyrosine derivatives which are potent, selective PPARγ agonists. Through the use of in vitro PPARγ binding and functional assays (2S)-3-(4- (benzyloxy)phenyl)-2-((1-methyl-3-oxo-3-phenylpropenyl)amino)propionic acid (2) was identified as a structurally novel PPARγ agonist. Structure-activity relationships identified the 2-aminobenzophenone moiety as a suitable isostere for the chemically labile enaminone moiety in compound 2, affording 2-((2-benzoylphenyl)amino)-3-(4-(benzyloxy)phenyl)propionic acid (9). Replacement of the benzyl group in 9 with substituents known to confer in vive potency in the thiazolidinedione (TZD) class of antidiabetic agents provided a dramatic increase in the in vitro functional potency and affinity at PPARγ, affording a series of potent and selective PPARγ agonists exemplified by (2S)-((2-benzoylphenyl)amino)-3-{4-[2-(methylpyridin-2- ylamino)ethoxy]phenyl}propionic acid (18), 3-{4-[2-(benzoxazol-2- ylmethylamino)ethoxy]phenyl}-(2S)-((2-benzoylphenyl)amino)propanoic acid (19), and (2S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-phenyloxazol-4- yl)ethoxy]phenyl}propanoic acid (20). Compounds 18 and 20 show potent antihyperglycemic and antihyperlipidemic activity when given orally in two rodent models of type 2 diabetes. In addition, these analogues are readily prepared in chiral nonracemic fashion from L-tyrosine and do not show a propensity to undergo racemization in vitro. The increased potency of these PPARγ agonists relative to troglitazone may translate into superior clinical efficacy for the treatment of type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)5020-5036
Number of pages17
JournalJournal of Medicinal Chemistry
Volume41
Issue number25
DOIs
StatePublished - Dec 3 1998

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Henke, B. R., Blanchard, S. G., Brackeen, M. F., Brown, K. K., Cobb, J. E., Collins, J. L., Harrington, W. W., Hashim, M. A., Hull-Ryde, E. A., Kaldor, I., Kliewer, S. A., Lake, D. H., Leesnitzer, L. M., Lehmann, J. M., Lenhard, J. M., Orband-Miller, L. A., Miller, J. F., Mook, R. A., Noble, S. A., ... Willson, T. M. (1998). N-(2-benzoylphenyl)-L-tyrosine PPARγ agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents. Journal of Medicinal Chemistry, 41(25), 5020-5036. https://doi.org/10.1021/jm9804127