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

Publication ,  Journal Article
Henke, BR; Blanchard, SG; Brackeen, MF; Brown, KK; Cobb, JE; Collins, JL; Harrington, WW; Hashim, MA; Hull-Ryde, EA; Kaldor, I; Kliewer, SA ...
Published in: J Med Chem
December 3, 1998

We have identified a novel series of antidiabetic N-(2-benzoylphenyl)-L-tyrosine derivatives which are potent, selective PPARgamma agonists. Through the use of in vitro PPARgamma binding and functional assays (2S)-3-(4-(benzyloxy)phenyl)-2-((1-methyl-3-oxo-3-phenylpropenyl)+ ++amin o)propionic acid (2) was identified as a structurally novel PPARgamma 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 vivo potency in the thiazolidinedione (TZD) class of antidiabetic agents provided a dramatic increase in the in vitro functional potency and affinity at PPARgamma, affording a series of potent and selective PPARgamma 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- benzoylph enyl)amino)propanoic acid (19), and (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]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 PPARgamma agonists relative to troglitazone may translate into superior clinical efficacy for the treatment of type 2 diabetes.

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Published In

J Med Chem

DOI

ISSN

0022-2623

Publication Date

December 3, 1998

Volume

41

Issue

25

Start / End Page

5020 / 5036

Location

United States

Related Subject Headings

  • Tyrosine
  • Transfection
  • Transcription Factors
  • Structure-Activity Relationship
  • Stereoisomerism
  • Recombinant Fusion Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Rats
  • Radioligand Assay
  • Propionates
 

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Henke, B. R., Blanchard, S. G., Brackeen, M. F., Brown, K. K., Cobb, J. E., Collins, J. L., … Willson, T. M. (1998). N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents. J Med Chem, 41(25), 5020–5036. https://doi.org/10.1021/jm9804127
Henke, B. R., S. G. Blanchard, M. F. Brackeen, K. K. Brown, J. E. Cobb, J. L. Collins, W. W. Harrington, et al. “N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents.J Med Chem 41, no. 25 (December 3, 1998): 5020–36. https://doi.org/10.1021/jm9804127.
Henke BR, Blanchard SG, Brackeen MF, Brown KK, Cobb JE, Collins JL, et al. N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents. J Med Chem. 1998 Dec 3;41(25):5020–36.
Henke, B. R., et al. “N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents.J Med Chem, vol. 41, no. 25, Dec. 1998, pp. 5020–36. Pubmed, doi:10.1021/jm9804127.
Henke BR, Blanchard SG, Brackeen MF, Brown KK, Cobb JE, Collins JL, Harrington WW, Hashim MA, Hull-Ryde EA, Kaldor I, Kliewer SA, Lake DH, Leesnitzer LM, Lehmann JM, Lenhard JM, Orband-Miller LA, Miller JF, Mook RA, Noble SA, Oliver W, Parks DJ, Plunket KD, Szewczyk JR, Willson TM. N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents. J Med Chem. 1998 Dec 3;41(25):5020–5036.
Journal cover image

Published In

J Med Chem

DOI

ISSN

0022-2623

Publication Date

December 3, 1998

Volume

41

Issue

25

Start / End Page

5020 / 5036

Location

United States

Related Subject Headings

  • Tyrosine
  • Transfection
  • Transcription Factors
  • Structure-Activity Relationship
  • Stereoisomerism
  • Recombinant Fusion Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Rats
  • Radioligand Assay
  • Propionates