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Cited by 301

The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.

N-(2-Benzoylphenyl)-l-tyrosine PPARγ Agonists. 1. Discovery of a Novel Series of Potent Antihyperglycemic and Antihyperlipidemic Agents

Open access
Henke, Brad R., Blanchard, Steven G., Brackeen, Marcus F., Brown, Kathleen K., Cobb, Jeff E., Collins, Jon L., Harrington,, W. Wallace, Hashim, Mir A., Hull-Ryde, Emily A., Kaldor, Istvan, Kliewer, Steven A., Lake, Debra H., Leesnitzer, Lisa M., Lehmann, Jürgen M., Lenhard, James M., Orband-Miller, Lisa A., Miller, John F., Mook,, Robert A., Noble, Stewart A., Oliver,, William, Parks, Derek J., Plunket, Kelli D., Szewczyk, Jerzy R., Willson, Timothy M.·1998·Journal of Medicinal Chemistry
DOI 10.1021/jm9804127
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Abstract

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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Metadata

Authors
Henke, B. R., Blanchard, S. G., Brackeen, M. F., Brown, K. K., Cobb, J. E., Collins, J. L., Harrington, 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, Noble, S. A., Oliver, Parks, D. J., Plunket, K. D., Szewczyk, J. R., & Willson, T. M.
Venue
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Published
1998-11-11
Volume
41
Issue
25
Pages
5020-5036
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
DOI
10.1021/jm9804127
OpenAlex
W1987652896
Cited by
301
References
38
FWCI
3.71
Type
journal article
Language
en
Open access
green

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