Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR)-Selective Agonists

Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic Acid (NEt-TMN)

Michael C. Heck, Carl Wagner, Pritika H. Shahani, Mairi Macneill, Aleksandra Grozic, Tamana Darwaiz, Micah Shimabuku, David G. Deans, Nathan M. Robinson, Samer H. Salama, Joseph W. Ziller, Ning Ma, Arjan Van Der Vaart, Pamela Marshall, Peter Jurutka

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Sulfonic acid analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene, 1) as well as seven novel and two reported analogues of 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN) were synthesized and assessed for selective retinoid X receptor (RXR) agonism. Compound 1 is FDA-approved for treatment of cutaneous T-cell lymphoma (CTCL); however, 1 can provoke side effects by impacting RXR-dependent receptor pathways. All of the analogues in this study were evaluated for their potential to bind RXR through modeling and then assayed in an RXR-RXR mammalian-2-hybrid (M2H) system and in RXR-responsive element (RXRE)-mediated transcriptional experiments. The EC50 profiles for these unique analogues and their analogous effectiveness to inhibit proliferation in CTCL cells relative to 1 suggest that these compounds possess similar or even enhanced therapeutic potential. Several compounds also displayed more selective RXR activation with minimal cross-signaling of the retinoic acid receptor. These results suggest that modifications of potent RXR agonists such as NEt-TMN can lead to improved biological selectivity and potency compared with the known therapeutic.

Original languageEnglish (US)
Pages (from-to)8924-8940
Number of pages17
JournalJournal of Medicinal Chemistry
Volume59
Issue number19
DOIs
StatePublished - Oct 13 2016

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Retinoid X Receptors
Benzoic Acid
Niacin
Cutaneous T-Cell Lymphoma
Retinoic Acid Receptors
Sulfonic Acids
bexarotene

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR)-Selective Agonists : Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic Acid (NEt-TMN). / Heck, Michael C.; Wagner, Carl; Shahani, Pritika H.; Macneill, Mairi; Grozic, Aleksandra; Darwaiz, Tamana; Shimabuku, Micah; Deans, David G.; Robinson, Nathan M.; Salama, Samer H.; Ziller, Joseph W.; Ma, Ning; Van Der Vaart, Arjan; Marshall, Pamela; Jurutka, Peter.

In: Journal of Medicinal Chemistry, Vol. 59, No. 19, 13.10.2016, p. 8924-8940.

Research output: Contribution to journalArticle

Heck, Michael C. ; Wagner, Carl ; Shahani, Pritika H. ; Macneill, Mairi ; Grozic, Aleksandra ; Darwaiz, Tamana ; Shimabuku, Micah ; Deans, David G. ; Robinson, Nathan M. ; Salama, Samer H. ; Ziller, Joseph W. ; Ma, Ning ; Van Der Vaart, Arjan ; Marshall, Pamela ; Jurutka, Peter. / Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR)-Selective Agonists : Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic Acid (NEt-TMN). In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 19. pp. 8924-8940.
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T2 - Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic Acid (NEt-TMN)

AU - Heck, Michael C.

AU - Wagner, Carl

AU - Shahani, Pritika H.

AU - Macneill, Mairi

AU - Grozic, Aleksandra

AU - Darwaiz, Tamana

AU - Shimabuku, Micah

AU - Deans, David G.

AU - Robinson, Nathan M.

AU - Salama, Samer H.

AU - Ziller, Joseph W.

AU - Ma, Ning

AU - Van Der Vaart, Arjan

AU - Marshall, Pamela

AU - Jurutka, Peter

PY - 2016/10/13

Y1 - 2016/10/13

N2 - Sulfonic acid analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene, 1) as well as seven novel and two reported analogues of 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN) were synthesized and assessed for selective retinoid X receptor (RXR) agonism. Compound 1 is FDA-approved for treatment of cutaneous T-cell lymphoma (CTCL); however, 1 can provoke side effects by impacting RXR-dependent receptor pathways. All of the analogues in this study were evaluated for their potential to bind RXR through modeling and then assayed in an RXR-RXR mammalian-2-hybrid (M2H) system and in RXR-responsive element (RXRE)-mediated transcriptional experiments. The EC50 profiles for these unique analogues and their analogous effectiveness to inhibit proliferation in CTCL cells relative to 1 suggest that these compounds possess similar or even enhanced therapeutic potential. Several compounds also displayed more selective RXR activation with minimal cross-signaling of the retinoic acid receptor. These results suggest that modifications of potent RXR agonists such as NEt-TMN can lead to improved biological selectivity and potency compared with the known therapeutic.

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