Mechanism of retinoid X receptor partial agonistic action of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5- carboxylic acid and structural development to increase potency

Fuminori Ohsawa, Shoya Yamada, Nobumasa Yakushiji, Ryosuke Shinozaki, Mariko Nakayama, Kohei Kawata, Manabu Hagaya, Toshiki Kobayashi, Kazutaka Kohara, Yuuki Furusawa, Chisa Fujiwara, Yui Ohta, Makoto Makishima, Hirotaka Naitou, Akihiro Tai, Yutaka Yoshikawa, Hiroyuki Yasui, Hiroki Kakuta

Research output: Contribution to journalArticle

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Abstract

We have reported that retinoid X receptor (RXR) partial agonist 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5- carboxylic acid (CBt-PMN, 4a) shows a significant antidiabetes effect in the KK-Ay type 2 diabetes model mice, with reduced side effects compared to RXR full agonists. To elucidate the mechanism of the RXR partial agonist activity of 4a, we synthesized derivatives of 4a, evaluated their RXR agonist activity, and performed structure-activity relationship analysis. Reporter gene assay revealed that though 6b, which possesses an amino group at the 2-position of 5-carboxybenzimidazole, showed RXR full-agonist activity, compounds 6d and 6e, which possess an oxygen atom and a sulfur atom at the corresponding position, respectively, showed weak RXR agonist activity. On the other hand, 6c, which has a trifluoromethyl group at the corresponding position, acts as an RXR partial agonist, having similar Emax (67 ± 2%) and lower EC50 (15 ± 0 nM) compared to those of 4a (Emax = 75 ± 4%, EC50 = 143 ± 2 nM). A fluorescence polarization assay of cofactor recruitment confirmed that fluorescein-labeled D22 coactivator peptide was less efficiently recruited to RXR by 4a and 6c than by LGD1069 (1), a known RXR full agonist. Electrostatic potential field calculations and computational docking studies suggested that full agonists show an electrostatic attraction, which stabilizes the holo structure and favors coactivator recruitment, between the side chain at the benzimidazole 2-position and the α-carbonyl oxygen of asparagine-306 in helix 4 (H4) of the RXR receptor. However, RXR partial agonists 4a and 6c lack this interaction. Like 4a, 6c showed a significant antidiabetes effect in KK-Ay type 2 diabetes model mice with reduced levels of the side effects associated with RXR full agonists. These findings should aid the design of new RXR partial agonists as antitype 2 diabetes drug candidates.

Original languageEnglish
Pages (from-to)1865-1877
Number of pages13
JournalJournal of Medicinal Chemistry
Volume56
Issue number5
DOIs
Publication statusPublished - Mar 14 2013

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Retinoid X Receptors
Static Electricity
1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid
Type 2 Diabetes Mellitus
Oxygen
Fluorescence Polarization
Asparagine
Structure-Activity Relationship
Fluorescein
Reporter Genes
Sulfur

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Mechanism of retinoid X receptor partial agonistic action of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5- carboxylic acid and structural development to increase potency. / Ohsawa, Fuminori; Yamada, Shoya; Yakushiji, Nobumasa; Shinozaki, Ryosuke; Nakayama, Mariko; Kawata, Kohei; Hagaya, Manabu; Kobayashi, Toshiki; Kohara, Kazutaka; Furusawa, Yuuki; Fujiwara, Chisa; Ohta, Yui; Makishima, Makoto; Naitou, Hirotaka; Tai, Akihiro; Yoshikawa, Yutaka; Yasui, Hiroyuki; Kakuta, Hiroki.

In: Journal of Medicinal Chemistry, Vol. 56, No. 5, 14.03.2013, p. 1865-1877.

Research output: Contribution to journalArticle

Ohsawa, F, Yamada, S, Yakushiji, N, Shinozaki, R, Nakayama, M, Kawata, K, Hagaya, M, Kobayashi, T, Kohara, K, Furusawa, Y, Fujiwara, C, Ohta, Y, Makishima, M, Naitou, H, Tai, A, Yoshikawa, Y, Yasui, H & Kakuta, H 2013, 'Mechanism of retinoid X receptor partial agonistic action of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5- carboxylic acid and structural development to increase potency', Journal of Medicinal Chemistry, vol. 56, no. 5, pp. 1865-1877. https://doi.org/10.1021/jm400033f
Ohsawa, Fuminori ; Yamada, Shoya ; Yakushiji, Nobumasa ; Shinozaki, Ryosuke ; Nakayama, Mariko ; Kawata, Kohei ; Hagaya, Manabu ; Kobayashi, Toshiki ; Kohara, Kazutaka ; Furusawa, Yuuki ; Fujiwara, Chisa ; Ohta, Yui ; Makishima, Makoto ; Naitou, Hirotaka ; Tai, Akihiro ; Yoshikawa, Yutaka ; Yasui, Hiroyuki ; Kakuta, Hiroki. / Mechanism of retinoid X receptor partial agonistic action of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5- carboxylic acid and structural development to increase potency. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 5. pp. 1865-1877.
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T1 - Mechanism of retinoid X receptor partial agonistic action of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5- carboxylic acid and structural development to increase potency

AU - Ohsawa, Fuminori

AU - Yamada, Shoya

AU - Yakushiji, Nobumasa

AU - Shinozaki, Ryosuke

AU - Nakayama, Mariko

AU - Kawata, Kohei

AU - Hagaya, Manabu

AU - Kobayashi, Toshiki

AU - Kohara, Kazutaka

AU - Furusawa, Yuuki

AU - Fujiwara, Chisa

AU - Ohta, Yui

AU - Makishima, Makoto

AU - Naitou, Hirotaka

AU - Tai, Akihiro

AU - Yoshikawa, Yutaka

AU - Yasui, Hiroyuki

AU - Kakuta, Hiroki

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N2 - We have reported that retinoid X receptor (RXR) partial agonist 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5- carboxylic acid (CBt-PMN, 4a) shows a significant antidiabetes effect in the KK-Ay type 2 diabetes model mice, with reduced side effects compared to RXR full agonists. To elucidate the mechanism of the RXR partial agonist activity of 4a, we synthesized derivatives of 4a, evaluated their RXR agonist activity, and performed structure-activity relationship analysis. Reporter gene assay revealed that though 6b, which possesses an amino group at the 2-position of 5-carboxybenzimidazole, showed RXR full-agonist activity, compounds 6d and 6e, which possess an oxygen atom and a sulfur atom at the corresponding position, respectively, showed weak RXR agonist activity. On the other hand, 6c, which has a trifluoromethyl group at the corresponding position, acts as an RXR partial agonist, having similar Emax (67 ± 2%) and lower EC50 (15 ± 0 nM) compared to those of 4a (Emax = 75 ± 4%, EC50 = 143 ± 2 nM). A fluorescence polarization assay of cofactor recruitment confirmed that fluorescein-labeled D22 coactivator peptide was less efficiently recruited to RXR by 4a and 6c than by LGD1069 (1), a known RXR full agonist. Electrostatic potential field calculations and computational docking studies suggested that full agonists show an electrostatic attraction, which stabilizes the holo structure and favors coactivator recruitment, between the side chain at the benzimidazole 2-position and the α-carbonyl oxygen of asparagine-306 in helix 4 (H4) of the RXR receptor. However, RXR partial agonists 4a and 6c lack this interaction. Like 4a, 6c showed a significant antidiabetes effect in KK-Ay type 2 diabetes model mice with reduced levels of the side effects associated with RXR full agonists. These findings should aid the design of new RXR partial agonists as antitype 2 diabetes drug candidates.

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