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Novel (2E,4E,6Z)-7-(2-Alkoxy-3,5-dialkylbenzene)-3-methylocta-2,4,6-trienoic Acid Retinoid X Receptor Modulators Are Active in Models of Type 2 Diabetes

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Department of Medicinal Chemistry, Ligand Pharmaceuticals, Incorporated, 10275 Science Center Drive, San Diego, California 92121
 To whom correspondence should be addressed. E-mail:  [email protected]
§  Department of Medicinal Chemistry, Ligand Pharmaceuticals, Inc., San Diego, CA.
Δ  Department of Pharmacology, Ligand Pharmaceuticals, Inc., San Diego, CA.
⊥  Current address: Conforma Therapeutics, San Diego, CA.
∇  Division of Endocrine Research, Lilly Research Laboratories, Indianapolis, IN.
‡  Process Chemistry Research, Lilly Research Laboratories, Indianapolis, IN.
‖  Current address:  Procter and Gamble, Cincinnati, OH.
†  Discovery Chemistry Research, Lilly Research Laboratories, Indianapolis, IN.
∞  Current address:  X-Ceptor Therapeutics, San Diego, CA.
✗  Current address, Genomics Institute of Norvartis Research Foundation, San Diego, CA.
+  Department of Molecular and Cell Biology, Ligand Pharmaceuticals Inc., San Diego, CA.
#  Department of New Leads Discovery, Ligand Pharmaceuticals, Inc., San Diego, CA.
◆  Current address:  Pfizer Inc., San Diego, CA.
·  Current address:  Roche Bioscience, Palo Alto, CA.
Cite this: J. Med. Chem. 2003, 46, 13, 2683–2696
Publication Date (Web):May 20, 2003
https://doi.org/10.1021/jm020340q
Copyright © 2003 American Chemical Society

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    Abstract

    Previous data have shown that RXR-selective agonists (e.g., 3 and 4) are insulin sensitizers in rodent models of non-insulin-dependent diabetes mellitus (NIDDM). Unfortunately, they also produce dramatic increases in triglycerides and profound suppression of the thyroid hormone axis. Here we describe the design and synthesis of new RXR modulators that retain the insulin-sensitizing activity of RXR agonists but produce substantially reduced side effects. These molecules bind selectively and with high affinity to RXR and, unlike RXR agonists, do not activate RXR homodimers. To further evaluate the antidiabetic activity of these RXR modulators, we have designed a concise and systematic structure−activity relationship around the 2E,4E,6Z-7-aryl-3-methylocta-2,4,6-trienoic acid scaffold. Selected compounds have been evaluated using insulin-resistant rodents (db/db mice) to characterize effects on glucose homeostasis. Our studies demonstrate the effectiveness of RXR modulators in lowering plasma glucose in the db/db mouse model.

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    HPLC trace of compounds 11a−g, 12a−e, and 13a−d. This material is available free of charge via the internet at http://pubs.acs.org.

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