The DOI matches its Crossref record; 5 of the 5 references it cites were found in a registry or an index.
Discovery of TAK-875: A Potent, Selective, and Orally Bioavailable GPR40 Agonist
Open accessAbstract
GPR40, one of the G protein-coupled receptors predominantly expressed in pancreatic β-cells, mediates enhancement of glucose-stimulated insulin secretion by free fatty acids. A potent and selective GPR40 agonist is theorized to be a safe and effective antidiabetic drug with little or no risk of hypoglycemia. Cyclization of the phenylpropanoic acid moiety of lead compound 1 produced fused phenylalkanoic acids with favorable in vitro agonist activities and pharmacokinetic profiles. Further optimization led to the discovery of dihydrobenzofuran derivative 9a ([(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate, TAK-875) as a potent, selective, and orally bioavailable GPR40 agonist, with a pharmacokinetic profile enabling long-acting drug efficacy. Compound 9a showed potent plasma glucose-lowering action and insulinotropic action during an oral glucose tolerance test in female Wistar fatty rats with impaired glucose tolerance. Compound 9a is currently in clinical trials for the treatment of type 2 diabetes mellitus.
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Brown, A. J., Goldsworthy, S. M., Barnes, A. A., Eilert, M. M., Tcheang, L., Daniels, D., Muir, A. I., Wigglesworth, M. J., Kinghorn, I., Fraser, N. J., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211609200 · Cited by 2,409
Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40
Itoh, Y., Kawamata, Y., Harada, M., Kobayashi, M., Fujii, R., Fukusumi, S., Ogi, K., Hosoya, M., Tanaka, Y., Uejima, H., et al. (2003) · Nature · doi:10.1038/nature01478 · Cited by 1,538
Fatty acid-induced β cell apoptosis: A link between obesity and diabetes
Shimabukuro, M., Zhou, Y.-T., Levi, M., & Unger, R. H. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.5.2498 · Cited by 1,142
Tzoulaki, I., Molokhia, M., Curcin, V., Little, M. P., Millett, C. J., Ng, A., Hughes, R. I., Khunti, K., Wilkins, M. R., Majeed, A., et al. (2009) · BMJ · doi:10.1136/bmj.b4731 · Cited by 444
Role of GPR40 in fatty acid action on the β cell line INS-1E
Shapiro, H., Shachar, S., Sekler, I., Hershfinkel, M., & Walker, M. D. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.07.042 · Cited by 220
Cited by
Free Fatty Acid Receptors in Health and Disease
Kimura, I., Ichimura, A., Ohue-Kitano, R., & Igarashi, M. (2020) · Physiological Reviews · doi:10.1152/physrev.00041.2018 · Cited by 1,018
High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875
Srivastava, A., Yano, J., Hirozane, Y., Kefala, G., Gruswitz, F., Snell, G., Lane, W., Ivetac, A., Aertgeerts, K., Nguyen, J., et al. (2014) · Nature · doi:10.1038/nature13494 · Cited by 340
Yashiro, H., Tsujihata, Y., Takeuchi, K., Hazama, M., Johnson, P. R. V., & Rorsman, P. (2012) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.111.187708 · Cited by 84
Self-citationLiu, T., Ji, R.-L., & Tao, Y.-X. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.108044 · Cited by 34
Deshmukh, A., Chang, K., Cuala, J., Hernandez Campos, M. J., Mahmood, S., Verma, R., Georgia, S., Loconte, V., & White, K. L. (2025) · Structure · doi:10.1016/j.str.2025.07.022 · Cited by 9
Chang, K., Deshmukh, A., Verma, R., Loconte, V., & White, K. L. (2026) · Structure · doi:10.1016/j.str.2026.03.005 · Cited by 3
Metadata
- Authors
- Negoro, N., Sasaki, S., Mikami, S., Ito, M., Suzuki, M., Tsujihata, Y., Ito, R., Harada, A., Takeuchi, K., Suzuki, N., Miyazaki, J., Santou, T., Odani, T., Kanzaki, N., Funami, M., Tanaka, T., Kogame, A., Matsunaga, S., Yasuma, T., & Momose, Y.
- Venue
- ACS Medicinal Chemistry Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2010-06-18
- Volume
- 1
- Issue
- 6
- Pages
- 290-294
- ISSN
- 1948-5875 (ISSN-L)
- OpenAlex
- W2054951377
- Cited by
- 246
- References
- 5
- FWCI
- 10.35
- Type
- journal article
- Language
- en
- Open access
- green
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