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 accessAbstract
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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Cites
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Cited by
Fat and Beyond: The Diverse Biology of PPARγ
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15-Deoxy-Δ12,14-prostaglandin J2-induced apoptosis does not require PPARγ in breast cancer cells
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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
- OpenAlex
- W1987652896
- Cited by
- 301
- References
- 38
- FWCI
- 3.71
- Type
- journal article
- Language
- en
- Open access
- green
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- CoChat. (2026). Citation check: N-(2-Benzoylphenyl)-l-tyrosine PPARγ Agonists. 1. Discovery of a Novel Series of Potent Antihyperglycemic and Antihyperlipidemic Agents. https://app.cochat.ai/papers/10.1021/jm9804127
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- 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., . . . 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. https://doi.org/10.1021/jm9804127
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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
