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).

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.

[1]  J. Cummings,et al.  Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer’s disease , 2016, Alzheimer's Research & Therapy.

[2]  Somy Yoon,et al.  HDAC and HDAC Inhibitor: From Cancer to Cardiovascular Diseases , 2016, Chonnam medical journal.

[3]  P. Jurutka,et al.  Analysis of differential secondary effects of novel rexinoids: select rexinoid X receptor ligands demonstrate differentiated side effect profiles , 2015, Pharmacology research & perspectives.

[4]  Arthur J. Olson,et al.  Distinguishing Binders from False Positives by Free Energy Calculations: Fragment Screening Against the Flap Site of HIV Protease , 2014, The journal of physical chemistry. B.

[5]  Craig D. Smith,et al.  Methyl Substitution of a Rexinoid Agonist Improves Potency and Reveals Site of Lipid Toxicity , 2014, Journal of medicinal chemistry.

[6]  K. Mcfarland,et al.  Low dose bexarotene treatment rescues dopamine neurons and restores behavioral function in models of Parkinson's disease. , 2013, ACS chemical neuroscience.

[7]  P. Jurutka,et al.  Modeling, synthesis, and biological evaluation of potential retinoid X receptor (RXR) selective agonists: novel analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphe , 2013, Journal of medicinal chemistry.

[8]  D. Wesson,et al.  Response to Comments on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models” , 2013, Science.

[9]  M. Makishima,et al.  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. , 2013, Journal of medicinal chemistry.

[10]  J. Cummings,et al.  A Review: Treatment of Alzheimer’s Disease Discovered in Repurposed Agents , 2013, Dementia and Geriatric Cognitive Disorders.

[11]  Hong-Qi Yang,et al.  Current advances in the treatment of Alzheimer's disease: focused on considerations targeting Aβ and tau , 2012, Translational Neurodegeneration.

[12]  P. Jurutka,et al.  Modeling, Synthesis and Biological Evaluation of Potential Retinoid X Receptor‐Selective Agonists: Novel Halogenated Analogues of 4‐[1‐(3,5,5,8,8‐Pentamethyl‐5,6,7,8‐tetrahydro‐2‐naphthyl)ethynyl]benzoic Acid (Bexarotene) , 2012, ChemMedChem.

[13]  Marcus D. Hanwell,et al.  Avogadro: an advanced semantic chemical editor, visualization, and analysis platform , 2012, Journal of Cheminformatics.

[14]  M. Gross.  Understanding amyloid and Alzheimer's disease , 2012, Current Biology.

[15]  M. Makishima,et al.  RXR Partial Agonist CBt-PMN Exerts Therapeutic Effects on Type 2 Diabetes without the Side Effects of RXR Full Agonists. , 2012, ACS medicinal chemistry letters.

[16]  M. Makishima,et al.  Feasibility of structural modification of retinoid X receptor agonists to separate blood glucose-lowering action from adverse effects: studies in KKA(y) type 2 diabetes model mice. , 2012, Biological & pharmaceutical bulletin.

[17]  Donald A. Wilson,et al.  ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models , 2012, Science.

[18]  Jing Chen,et al.  (+)-Rutamarin as a Dual Inducer of Both GLUT4 Translocation and Expression Efficiently Ameliorates Glucose Homeostasis in Insulin-Resistant Mice , 2012, PloS one.

[19]  H. Wakelee,et al.  The effect of bexarotene on atorvastatin pharmacokinetics: results from a phase I trial of bexarotene plus chemotherapy in patients with advanced non-small cell lung cancer , 2012, Cancer Chemotherapy and Pharmacology.

[20]  Chris Morley,et al.  Open Babel: An open chemical toolbox , 2011, J. Cheminformatics.

[21]  H. Kagechika,et al.  Diphenylamine-based retinoid antagonists: regulation of RAR and RXR function depending on the N-substituent. , 2011, Bioorganic & medicinal chemistry.

[22]  J. Kolesar,et al.  A Pilot, First-in-Human, Pharmacokinetic Study of 9cUAB30 in Healthy Volunteers , 2010, Cancer Prevention Research.

[23]  M. Makishima,et al.  Modification at the acidic domain of RXR agonists has little effect on permissive RXR-heterodimer activation. , 2010, Bioorganic & medicinal chemistry letters.

[24]  M. Makishima,et al.  Modification at the Lipophilic Domain of RXR Agonists Differentially Influences Activation of RXR Heterodimers. , 2010, ACS medicinal chemistry letters.

[25]  M. Privalsky,et al.  DNA recognition by thyroid hormone and retinoic acid receptors: 3,4,5 rule modified , 2010, Molecular and Cellular Endocrinology.

[26]  Philip E. Bourne,et al.  A Multidimensional Strategy to Detect Polypharmacological Targets in the Absence of Structural and Sequence Homology , 2010, PLoS Comput. Biol..

[27]  David S. Goodsell,et al.  AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility , 2009, J. Comput. Chem..

[28]  P. Jurutka,et al.  Modeling, synthesis and biological evaluation of potential retinoid X receptor (RXR) selective agonists: novel analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene). , 2009, Journal of medicinal chemistry.

[29]  H. Gronemeyer,et al.  Silicon Analogues of the RXR‐Selective Retinoid Agonist SR11237 (BMS649): Chemistry and Biology , 2009, ChemMedChem.

[30]  Yang Li,et al.  Identification of a PPARdelta agonist with partial agonistic activity on PPARgamma. , 2009, Bioorganic & medicinal chemistry letters.

[31]  H. Gronemeyer,et al.  Modulating retinoid X receptor with a series of (E)-3-[4-hydroxy-3-(3-alkoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl]acrylic acids and their 4-alkoxy isomers. , 2009, Journal of medicinal chemistry.

[32]  Y. Hamuro,et al.  Structure of the intact PPAR-γ–RXR-α nuclear receptor complex on DNA , 2008, Nature.

[33]  Pamela A Marshall,et al.  Using Saccharomyces cerevisiae to test the mutagenicity of household compounds: an open ended hypothesis-driven teaching lab. , 2007, CBE life sciences education.

[34]  H. Gronemeyer,et al.  Modulators of the structural dynamics of the retinoid X receptor to reveal receptor function , 2007, Proceedings of the National Academy of Sciences.

[35]  L. Altucci,et al.  RAR and RXR modulation in cancer and metabolic disease , 2007, Nature Reviews Drug Discovery.

[36]  E. Dmitrovsky,et al.  A Proof-of-Principle Clinical Trial of Bexarotene in Patients with Non–Small Cell Lung Cancer , 2007, Clinical Cancer Research.

[37]  T. Tollefsbol,et al.  The low-toxicity 9-cis UAB30 novel retinoid down-regulates the DNA methyltransferases and has anti-telomerase activity in human breast cancer cells. , 2007, International journal of oncology.

[38]  W. Lamph,et al.  Differentiation and growth inhibition mediated via the RXR:PPARgamma heterodimer in colon cancer. , 2006, Cancer letters.

[39]  J. Montana,et al.  Synthesis, Crystal Structure Analysis, and Pharmacological Characterization of Disila-bexarotene, a Disila-Analogue of the RXR-Selective Retinoid Agonist Bexarotene , 2005 .

[40]  W. Lamph,et al.  A Selective Retinoid X Receptor Agonist Bexarotene (Targretin) Prevents and Overcomes Acquired Paclitaxel (Taxol) Resistance in Human Non–Small Cell Lung Cancer , 2004, Clinical Cancer Research.

[41]  W. Lamph,et al.  Synergistic effect of a retinoid X receptor-selective ligand bexarotene (LGD1069, Targretin) and paclitaxel (Taxol) in mammary carcinoma , 2004, Breast Cancer Research and Treatment.

[42]  F. Field,et al.  LXR/RXR ligand activation enhances basolateral efflux of beta-sitosterol in CaCo-2 cells. , 2004, Journal of lipid research.

[43]  M. D. Leibowitz,et al.  Design, synthesis and structure-activity relationship of novel RXR-selective modulators. , 2004, Bioorganic & medicinal chemistry letters.

[44]  H. Xu,et al.  Structure-based design of potent retinoid X receptor alpha agonists. , 2004, Journal of medicinal chemistry.

[45]  Stefan Svensson,et al.  Crystal structure of the heterodimeric complex of LXRα and RXRβ ligand‐binding domains in a fully agonistic conformation , 2003, The EMBO journal.

[46]  K. Bland,et al.  Conformationally defined retinoic acid analogues. 5. Large-scale synthesis and mammary cancer chemopreventive activity for (2E,4E,6Z,8E)-8-(3',4'-dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid (9cUAB30). , 2003, Journal of medicinal chemistry.

[47]  M. D. Leibowitz,et al.  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. , 2003, Journal of medicinal chemistry.

[48]  H. Samuels,et al.  Functional Evidence for Retinoid X Receptor (RXR) as a Nonsilent Partner in the Thyroid Hormone Receptor/RXR Heterodimer , 2002, Molecular and Cellular Biology.

[49]  F. Field,et al.  LXR/RXR activation enhances basolateral efflux of cholesterol in CaCo-2 cells DOI 10.1194/jlr.M100358-JLR200 , 2002, Journal of Lipid Research.

[50]  D. Moras,et al.  Molecular recognition of agonist ligands by RXRs. , 2002, Molecular endocrinology.

[51]  R. Evans,et al.  The Structural Basis for the Specificity of Retinoid-X Receptor-selective Agonists: New Insights Into the Role of Helix H12* , 2002, The Journal of Biological Chemistry.

[52]  J. Olefsky,et al.  Nuclear Receptor Minireview Series* , 2001, The Journal of Biological Chemistry.

[53]  M. Galligan,et al.  Distinct retinoid X receptor activation function-2 residues mediate transactivation in homodimeric and vitamin D receptor heterodimeric contexts. , 2001, Journal of molecular endocrinology.

[54]  M. Faul,et al.  Synthesis of novel retinoid X receptor-selective retinoids. , 2001, The Journal of organic chemistry.

[55]  R. Chandraratna,et al.  Enantioselective syntheses of potent retinoid X receptor ligands: differential biological activities of individual antipodes. , 2001, Journal of medicinal chemistry.

[56]  U. Reichert,et al.  Retinoid-dependent growth inhibition, differentiation and apoptosis in acute promyelocytic leukemia cells. Expression and activation of caspases , 2000, Cell Death and Differentiation.

[57]  J. B. Tillman,et al.  Vitamin D receptor displays DNA binding and transactivation as a heterodimer with the retinoid X receptor, but not with the thyroid hormone receptor , 1999, Journal of cellular biochemistry.

[58]  B. Haugen,et al.  Central hypothyroidism associated with retinoid X receptor-selective ligands. , 1999, The New England journal of medicine.

[59]  L. Freedman,et al.  Thyroid hormone receptor does not heterodimerize with the vitamin D receptor but represses vitamin D receptor-mediated transactivation. , 1998, Molecular endocrinology.

[60]  Y. Hashimoto,et al.  Potent retinoid synergists with a diphenylamine skeleton. , 1998, Biological & pharmaceutical bulletin.

[61]  M. Taimi,et al.  Conformationally defined retinoic acid analogues. 4. Potential new agents for acute promyelocytic and juvenile myelomonocytic leukemias. , 1998, Journal of medicinal chemistry.

[62]  M. Haussler,et al.  Heterodimeric DNA Binding by the Vitamin D Receptor and Retinoid X Receptors Is Enhanced by 1,25-Dihydroxyvitamin D3 and Inhibited by 9-cis-Retinoic Acid , 1998, The Journal of Biological Chemistry.

[63]  R. Chandraratna,et al.  Receptor specificity of retinoid-induced epidermal hyperplasia: effect of RXR-selective agonists and correlation with topical irritation. , 1997, The Journal of pharmacology and experimental therapeutics.

[64]  L. Hamann,et al.  Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists , 1997, Nature.

[65]  L. Dardashti,et al.  Activation of specific RXR heterodimers by an antagonist of RXR homodimers , 1996, Nature.

[66]  Y. Liu,et al.  Vitamin D Receptors Repress Basal Transcription and Exert Dominant Negative Activity on Triiodothyronine-mediated Transcriptional Activity (*) , 1996, The Journal of Biological Chemistry.

[67]  L. Freedman,et al.  Selective effects of ligands on vitamin D3 receptor- and retinoid X receptor-mediated gene activation in vivo , 1996, Molecular and cellular biology.

[68]  R. Evans,et al.  The RXR heterodimers and orphan receptors , 1995, Cell.

[69]  M. Pfahl,et al.  Conformational effects on retinoid receptor selectivity. 2. Effects of retinoid bridging group on retinoid X receptor activity and selectivity. , 1995, Journal of medicinal chemistry.

[70]  M. Boehm,et al.  Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells. , 1995, Journal of medicinal chemistry.

[71]  Lin Zhang,et al.  Syntheses of isotopically labeled 4‐[1‐(3,5,5,8,8‐pentamethyl‐5,6,7,8‐tetrahydro‐2‐naphthyl)ethenyl]benzoic acid (LGD1069), a potent retinoid x receptor‐selective ligand , 1995 .

[72]  K. Umesono,et al.  Unique response pathways are established by allosteric interactions among nuclear hormone receptors , 1995, Cell.

[73]  L Zhang,et al.  Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids. , 1994, Journal of medicinal chemistry.

[74]  J. Lehmann,et al.  Formation of retinoid X receptor homodimers leads to repression of T3 response: hormonal cross talk by ligand-induced squelching , 1993, Molecular and cellular biology.

[75]  J. Lehmann,et al.  Conformational effects on retinoid receptor selectivity. 1. Effect of 9-double bond geometry on retinoid X receptor activity. , 1993, Journal of medicinal chemistry.

[76]  M. Galligan,et al.  Retinoid X receptors stimulate and 9-cis retinoic acid inhibits 1,25-dihydroxyvitamin D3-activated expression of the rat osteocalcin gene , 1993, Molecular and cellular biology.

[77]  K. Umesono,et al.  Determinants for selective RAR and TR recognition of direct repeat HREs. , 1993, Genes & development.

[78]  J. Lehmann,et al.  Retinoids selective for retinoid X receptor response pathways. , 1992, Science.

[79]  W. Goddard,et al.  UFF, a full periodic table force field for molecular mechanics and molecular dynamics simulations , 1992 .

[80]  P. Chambon,et al.  Multiplicity generates diversity in the retinoic acid signalling pathways. , 1992, Trends in biochemical sciences.

[81]  H. Samuels,et al.  A domain containing leucine-zipper-like motifs mediate novel in vivo interactions between the thyroid hormone and retinoic acid receptors. , 1989, Molecular endocrinology.

[82]  R. Kern,et al.  A yeast strain for simultaneous detection of induced mitotic crossing over, mitotic gene conversion and reverse mutation , 1975 .

[83]  F. Zimmermann.  Procedures used in the induction of mitotic recombination and mutation in the yeast Saccharomyces cerevisiae. , 1975, Mutation research.

[84]  Craig D. Smith,et al.  Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention. , 2014, Bioorganic & medicinal chemistry.