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Itoh T.,Laboratory of Drug Design and Medicinal Chemistry | Yoshimoto N.,Showa Pharmaceutical University | Yamamoto K.,Laboratory of Drug Design and Medicinal Chemistry | Yamamoto K.,Showa Pharmaceutical University
Heterocycles | Year: 2010

To study structure-activity relationships of oxidized fatty acids for the activation of peroxisome proliferator-activated receptors (PPARs), which are ligand-dependent transcription factors, we synthesized a series of oxidized fatty acids via iodolactone as a key intermediate. © 2010 The Japan Institute of Heterocyclic Chemistry.

Yoshimoto N.,Laboratory of Drug Design and Medicinal Chemistry | Yoshimoto N.,Showa Pharmaceutical University | Sakamaki Y.,Laboratory of Drug Design and Medicinal Chemistry | Sakamaki Y.,Tokyo Medical and Dental University | And 8 more authors.
Journal of Medicinal Chemistry | Year: 2012

Previously, we reported that 22S-butyl-25,26,27-trinor-1α24- dihydroxyvitamin D 32 represents a new class of antagonist for the vitamin D receptor (VDR). The crystal structure of the ligand-binding domain (LBD) of VDR complexed with 2 showed the formation of a butyl pocket to accommodate the 22-butyl group and insufficient interactions between ligand 2 and the C-terminus of VDR. Here, we designed and synthesized new analogues 5a-c and evaluated their biological activities to probe whether agonistic activity is recovered when the analogue restores interactions with the C-terminus of VDR. Analogues 5a-c exhibited full agonistic activity in transactivation. Interestingly, 5c, which bears a 24-diethyl group, completely recovered agonistic activity, although 3c and 4c act as an antagonist and a weak agonist, respectively. The crystal structures of VDR-LBD complexed with 3a, 4a, 5a, and 5c were solved, and the results confirmed that butyl pocket formation in VDR strongly affects the agonistic or antagonistic behaviors of ligands. © 2012 American Chemical Society.

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