Skip to main content
SpringerLink
Log in

Strategies for the Design of Vitamin D Receptor Ligands

  • Chapter
  • First Online:
Nuclear Receptors

  • 804 Accesses

Abstract

Structure-activity relationship analysis is a powerful tool to elucidate the structural requirements for high-affinity vitamin D receptor (VDR) ligands. This chapter systematically interrogates the structural features of 1α,25(OH)2D3, the vitamin D metabolite with the highest VDR affinity. It can be concluded that the C1α and C25 hydroxyl groups of 1α,25(OH)2D3 are very important for binding. Optimal spatial arrangement of both hydroxyl groups was achieved with either a hydrophobic semi-flexible secosteroid scaffold or a simplified, flexible carbon chain. Y-shaped ligands with high affinity confirmed a highly inducible VDR ligand-binding pocket, which has been visualized by X-ray crystallography. Substitution of the secosteroid scaffold by other hydrophobic spacers such as carboranes or aromatic ring systems has led to many non-secosteroid VDR ligands. Exploration of ligand substitution has led to the development of antagonists that are accommodated by the inducible VDR ligand-binding pocket but alter the overall conformation of VDR in ways that prevent interactions with coactivator proteins from occurring and ultimately result in reduced gene transcription.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 279.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Steenbock H, Black A. Fat-soluble vitamins. XVII. The induction of growthpromoting and calcifying properties in a ration by exposure to ultraviolet light. J Biol Chem. 1924;61:405–22.

    Article  CAS  Google Scholar 

  2. Askew FA, Bourdillon RB, Bruce HM, Jenkins RGC, Webster TA. The distillation of vitamin D. Proc R Soc. 1930;B107:76–90.

    Google Scholar 

  3. Chalk KJ, Kodicek E. The association of 14C-labelled vitamin D2 with rat serum proteins. Biochem J. 1961;79:1–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Blunt JW, DeLuca HF, Schnoes HK. 25-hydroxycholecalciferol. A biologically active metabolite of vitamin D3. Biochemistry. 1968;7(10):3317–22.

    Article  CAS  PubMed  Google Scholar 

  5. Holick MF, Schnoes HK, DeLuca HF, Suda T, Cousins RJ. Isolation and identification of 1,25-dihydroxycholecalciferol. A metabolite of vitamin D active in intestine. Biochemistry. 1971;10(14):2799–804.

    Article  CAS  PubMed  Google Scholar 

  6. Brumbaugh PF, Haussler MR. 1Alpha,25-dihydroxyvitamin D3 receptor: competitive binding of vitamin D analogs. Life Sci. 1973;13(12):1737–46.

    Article  CAS  PubMed  Google Scholar 

  7. McDonnell DP, Mangelsdorf DJ, Pike JW, Haussler MR, O’Malley BW. Molecular cloning of complementary DNA encoding the avian receptor for vitamin D. Science. 1987;235(4793):1214–7.

    Article  CAS  PubMed  Google Scholar 

  8. Wang YJ, Zhu JG, DeLuca HF. Where is the vitamin D receptor? Arch Biochem Biophys. 2012;523(1):123–33.

    Article  CAS  PubMed  Google Scholar 

  9. Huhtakangas JA, Olivera CJ, Bishop JE, Zanello LP, Norman AW. The vitamin D receptor is present in caveolae-enriched plasma membranes and binds 1 alpha,25(OH)(2)-vitamin D-3 in vivo and in vitro. Mol Endocrinol. 2004;18(11):2660–71.

    Article  CAS  PubMed  Google Scholar 

  10. Orlov I, Rochel N, Moras D, Klaholz BP. Structure of the full human RXR/VDR nuclear receptor heterodimer complex with its DR3 target DNA. EMBO J. 2012;31(2):291–300.

    Article  CAS  PubMed  Google Scholar 

  11. Haussler MR, Jurutka PW, Mizwicki M, Norman AW. Vitamin D receptor (VDR)-mediated actions of 1 alpha,25(OH)(2)vitarnin D-3: genomic and non-genomic mechanisms. Best Pract Res Clin Endocrinol Metab. 2011;25(4):543–59.

    Article  CAS  PubMed  Google Scholar 

  12. White JH, Salehi-Tabar R, Dimitrow V, Bouttier M. Diverse mechanism of transcriptional regulation by the vitamin D receptor. In: Feldman D, editor. Vitamin D, vol. 1. 4th ed. London: Elsevier; 2018. p. 175–87.

    Chapter  Google Scholar 

  13. Nurminen V, Neme A, Seuter S, Carlberg C. The impact of the vitamin D-modulated epigenome on VDR target gene regulation. Biochim Biophys Acta. 2018;1861(8):697–705.

    Article  CAS  Google Scholar 

  14. Verlinden L, Bouillon R, De Clercq P, Verstuyf A. Analogs of calcitriol. In: Feldman D, editor. Vitamin D, vol. 2. 4th ed. Academic Press, Elsevier; 2018. p. 583–611.

    Google Scholar 

  15. Stites RE, Mackrell JG, Stayrock KR. Nonsecosteroidal ligands and molulators of the vitamin D receptor. In: Feldman D, editor. Vitamin D, vol. 2. Academic Press, Elsevier; 2018. p. 615–25.

    Google Scholar 

  16. Makishima M, Yamada S. Bile acid-derived vitamin D receptor ligands. In: Feldman D, editor. Vitamin D, vol. 2. Academic Press, Elsevier; 2018. p. 629–41.

    Google Scholar 

  17. Yu OB, Arnold LA. Moldulating vitamin D receptor-coregulator binding with small molecules. In: Feldman D, editor. Vitamin D, vol. 2. Academic Press, Elsevier; 2018. p. 657–64.

    Google Scholar 

  18. Saitoh H. Vitamin D receptor antagonists. In: Feldman D, editor. Vitamin D, vol. 2. Academic Press, Elsevier; 2018. p. 679–91.

    Google Scholar 

  19. Maestro MA, Molnar F, Carlberg C. Vitamin D and its synthetic analogs. J Med Chem. 2019;62(15):6854–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Maestro MA, Molnar F, Mourino A, Carlberg C. Vitamin D receptor 2016: novel ligands and structural insights. Expert Opin Ther Pat. 2016;26(11):1291–306.

    Article  CAS  PubMed  Google Scholar 

  21. Plonska-Ocypa K, Grzywacz P, Sicinski RR, Plum LA, DeLuca HF. Synthesis and biological evaluation of a des-C,D-analog of 2-methylene-19-nor-1alpha,25-(OH)2D3. J Steroid Biochem Mol Biol. 2007;103(3–5):298–304.

    Article  CAS  PubMed  Google Scholar 

  22. Mottershead DG, Polly P, Lyons RJ, Sutherland RL, Watts CK. High activity, soluble, bacterially expressed human vitamin D receptor and its ligand binding domain. J Cell Biochem. 1996;61(3):325–37.

    Article  CAS  PubMed  Google Scholar 

  23. Molnar F, Sigueiro R, Sato Y, Araujo C, Schuster I, Antony P, et al. 1alpha,25(OH)2-3-epi-vitamin D3, a natural physiological metabolite of vitamin D3: its synthesis, biological activity and crystal structure with its receptor. PLoS One. 2011;6(3):e18124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Monkawa T, Yoshida T, Wakino S, Shinki T, Anazawa H, Deluca HF, et al. Molecular cloning of cDNA and genomic DNA for human 25-hydroxyvitamin D3 1 alpha-hydroxylase. Biochem Biophys Res Commun. 1997;239(2):527–33.

    Article  CAS  PubMed  Google Scholar 

  25. Takeyama K, Kitanaka S, Sato T, Kobori M, Yanagisawa J, Kato S. 25-Hydroxyvitamin D3 1alpha-hydroxylase and vitamin D synthesis. Science. 1997;277(5333):1827–30.

    Article  CAS  PubMed  Google Scholar 

  26. St-Arnaud R, Messerlian S, Moir JM, Omdahl JL, Glorieux FH. The 25-hydroxyvitamin D 1-alpha-hydroxylase gene maps to the pseudovitamin D-deficiency rickets (PDDR) disease locus. J Bone Miner Res. 1997;12(10):1552–9.

    Article  CAS  PubMed  Google Scholar 

  27. Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, Stewart PM, et al. Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab. 2001;86(2):888–94.

    CAS  PubMed  Google Scholar 

  28. Norman AW, Bouillon R, Farach-Carson MC, Bishop JE, Zhou LX, Nemere I, et al. Demonstration that 1 beta,25-dihydroxyvitamin D3 is an antagonist of the nongenomic but not genomic biological responses and biological profile of the three A-ring diastereomers of 1 alpha,25-dihydroxyvitamin D3. J Biol Chem. 1993;268(27):20022–30.

    Article  CAS  PubMed  Google Scholar 

  29. Bischof MG, Siu-Caldera ML, Weiskopf A, Vouros P, Cross HS, Peterlik M, et al. Differentiation-related pathways of 1 alpha,25-dihydroxycholecalciferol metabolism in human colon adenocarcinoma-derived Caco-2 cells: production of 1 alpha,25-dihydroxy-3epi-cholecalciferol. Exp Cell Res. 1998;241(1):194–201.

    Article  CAS  PubMed  Google Scholar 

  30. Paaren HE, Schoenen HK, DeLuca HF. Synthesis of 1β-hydroxyvitamin D3 and 1β,25-dihydroxyvitamin D3. Chem Commun. 1977;23:890–2.

    Article  Google Scholar 

  31. Pauwels S, Jans I, Billen J, Heijboer A, Verstuyf A, Carmeliet G, et al. 1beta,25-Dihydroxyvitamin D3: a new vitamin D metabolite in human serum. J Steroid Biochem Mol Biol. 2017;173:341–8.

    Article  CAS  PubMed  Google Scholar 

  32. Wecksler WR, Norman AW. Studies on the mode of action of calciferol XXV. 1 alpha,25-dihydroxy-5,6-trans-vitamin D3, the 5E-isomer of 1 alpha,25-dihydroxyvitamin D3. Steroids. 1980;35(4):419–25.

    Article  CAS  PubMed  Google Scholar 

  33. Kobayashi T, Moriuchi S, Shimura F, Katsui G. Synthesis and biological activity of 5,6-trans-vitamin D3 in anephric rats. J Nutr Sci Vitaminol (Tokyo). 1976;22(4):299–306.

    Article  CAS  Google Scholar 

  34. VanAlstyne EM, Norman AW, Okamura WH. 7,8-Cis geometric isomers of the steroid hormone 1a,25-dihydroxyvitamin D. J Am Chem Soc. 1994;116:6207–16.

    Article  CAS  Google Scholar 

  35. Maynard DF, Trankle WG, Norman AW, Okamura WH. 14-epi stereoisomers of 25-hydroxy- and 1 alpha,25-dihydroxyvitamin D3: synthesis, isomerization to previtamins, and biological studies. J Med Chem. 1994;37(15):2387–93.

    Article  CAS  PubMed  Google Scholar 

  36. Kurek-Tyrlik A, Michalak K, Wicha J. Synthesis of 17-epi-calcitriol from a common androstane derivative, involving the ring B photochemical opening and the intermediate triene ozonolysis. J Org Chem. 2005;70(21):8513–21.

    Article  CAS  PubMed  Google Scholar 

  37. Michalak K, Wicha J. Total synthesis of a CD-ring: side-chain building block for preparing 17-epi-calcitriol derivatives from the Hajos-Parrish dione. J Org Chem. 2011;76(16):6906–11.

    Article  CAS  PubMed  Google Scholar 

  38. Binderup L, Latini S, Binderup E, Bretting C, Calverley M, Hansen K. 20-epi-vitamin D3 analogues: a novel class of potent regulators of cell growth and immune responses. Biochem Pharmacol. 1991;42(8):1569–75.

    Article  CAS  PubMed  Google Scholar 

  39. Zhou X, Zhu GD, Van Haver D, Vandewalle M, De Clercq PJ, Verstuyf A, et al. Synthesis, biological activity, and conformational analysis of four seco-D-15,19-bisnor-1alpha,25-dihydroxyvitamin D analogues, diastereomeric at C17 and C20. J Med Chem. 1999;42(18):3539–56.

    Article  CAS  PubMed  Google Scholar 

  40. Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006;84(1):18–28.

    Article  CAS  PubMed  Google Scholar 

  41. Procsal DA, Okamura WH, Norman AW. Structural requirements for the interaction of 1 alpha, 25-(OH) 2- vitiamin D3 with its chick interestinal receptor system. J Biol Chem. 1975;250(21):8382–8.

    Article  CAS  PubMed  Google Scholar 

  42. Perlman KL, Sicinski RR, Schnoes HK, DeLuca HF. 1α,25-dihydroxy-19-nor-vitamin D3, a novel vitamin D-related compound with potential therapeutic activity. Tetrahedron Lett. 1990;31(13):1823–4.

    Article  CAS  Google Scholar 

  43. Bouillon R, Sarandeses LA, Allewaert K, Zhao J, Mascarenas JL, Mourino A, et al. Biologic activity of dihydroxylated 19-nor-(pre)vitamin D3. J Bone Miner Res. 1993;8(8):1009–15.

    Article  CAS  PubMed  Google Scholar 

  44. Sicinski RR, Perlman KL, Prahl J, Smith C, DeLuca HF. Synthesis and biological activity of 1 alpha, 25-dihydroxy-18-norvitamin D3 and 1 alpha, 25-dihydroxy-18,19-dinorvitamin D3. J Med Chem. 1996;39(22):4497–506.

    Article  CAS  PubMed  Google Scholar 

  45. Kubodera N, Miyamoto K, Matsumoto M, Kawanishi T, Ohkawa H, Mori T. Synthetic studies of vitamin D analogues. X. Synthesis and biological activities of 1 alpha,25-dihydroxy-21-norvitamin D3. Chem Pharm Bull (Tokyo). 1992;40(3):648–51.

    Article  CAS  Google Scholar 

  46. Ostrem VK, Lau WF, Lee SH, Perlman K, Prahl J, Schnoes HK, et al. Induction of monocytic differentiation of HL-60 cells by 1,25-dihydroxyvitamin D analogs. J Biol Chem. 1987;262(29):14164–71.

    Article  CAS  PubMed  Google Scholar 

  47. Sakamaki Y, Inaba Y, Yoshimoto N, Yamamoto K. Potent antagonist for the vitamin D receptor: vitamin D analogues with simple side chain structure. J Med Chem. 2010;53(15):5813–26.

    Article  CAS  PubMed  Google Scholar 

  48. Haussler MR, Zerwekh JE, Hesse RH, Rizzardo E, Pechet MM. Biological activity of 1alpha-hydroxycholecalciferol, a synthetic analog of the hormonal form of vitamin D3. Proc Natl Acad Sci U S A. 1973;70(8):2248–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Holick MF, Semmler EJ, Schnoes HK, DeLuca HF. 1 Hydroxy derivative of vitamin D3 : a highly potent analog of 1, 25-dihydroxyvitamin D3. Science. 1973;180(4082):190–1.

    Article  CAS  PubMed  Google Scholar 

  50. Verstuyf A, Verlinden L, van Etten E, Shi L, Wu Y, D'Halleweyn C, et al. Biological activity of CD-ring modified 1alpha,25-dihydroxyvitamin D analogues: C-ring and five-membered D-ring analogues. J Bone Miner Res. 2000;15(2):237–52.

    Article  CAS  PubMed  Google Scholar 

  51. Kutner A, Zhao H, Fitak H, Chodyn M, Halkes SJ, Wilson SR, et al. Inventors new pharmaceutically active compounds. 1995. Patent, WO1995019963A1.

    Google Scholar 

  52. Rochel N, Wurtz JM, Mitschler A, Klaholz B, Moras D. The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand. Mol Cell. 2000;5(1):173–9.

    Article  CAS  PubMed  Google Scholar 

  53. Kakuda S, Okada K, Eguchi H, Takenouchi K, Hakamata W, Kurihara M, et al. Structure of the ligand-binding domain of rat VDR in complex with the nonsecosteroidal vitamin D3 analogue YR301. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2008;64(Pt 11):970–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Boehm MF, Fitzgerald P, Zou A, Elgort MG, Bischoff ED, Mere L, et al. Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1,25-dihydroxyvitamin D3. Chem Biol. 1999;6(5):265–75.

    Article  CAS  PubMed  Google Scholar 

  55. Hakamata W, Sato Y, Okuda H, Honzawa S, Saito N, Kishimoto S, et al. (2S,2'R)-analogue of LG190178 is a major active isomer. Bioorg Med Chem Lett. 2008;18(1):120–3.

    Article  CAS  PubMed  Google Scholar 

  56. Kashiwagi H, Ono Y, Ohta M, Morikami K, Takahashi T. Systematic SAR study of the side chain of nonsecosteroidal vitamin D(3) analogs. Bioorg Med Chem. 2012;20(14):4495–506.

    Article  CAS  PubMed  Google Scholar 

  57. Kashiwagi H, Ohta M, Ono Y, Morikami K, Itoh S, Sato H, et al. Effects of fluorines on nonsecosteroidal vitamin D receptor agonists. Bioorg Med Chem. 2013;21(3):712–21.

    Article  CAS  PubMed  Google Scholar 

  58. Ge Z, Hao M, Xu M, Su Z, Kang Z, Xue L, et al. Novel nonsecosteroidal VDR ligands with phenyl-pyrrolyl pentane skeleton for cancer therapy. Eur J Med Chem. 2016;107:48–62.

    Article  CAS  PubMed  Google Scholar 

  59. Taniguchi K, Katagiri K, Kashiwagi H, Harada S, Sugimoto Y, Shimizu Y, et al. A novel nonsecosteroidal VDR agonist (CH5036249) exhibits efficacy in a spontaneous benign prostatic hyperplasia beagle model. J Steroid Biochem Mol Biol. 2010;121(1–2):204–7.

    Article  CAS  PubMed  Google Scholar 

  60. Fujii S, Masuno H, Taoda Y, Kano A, Wongmayura A, Nakabayashi M, et al. Boron cluster-based development of potent nonsecosteroidal vitamin D receptor ligands: direct observation of hydrophobic interaction between protein surface and carborane. J Am Chem Soc. 2011;133(51):20933–41.

    Article  CAS  PubMed  Google Scholar 

  61. Fujii S, Kano A, Masuno H, Songkram C, Kawachi E, Hirano T, et al. Design and synthesis of tetraol derivatives of 1,12-dicarba-closo-dodecaborane as non-secosteroidal vitamin D analogs. Bioorg Med Chem Lett. 2014;24(18):4515–9.

    Article  CAS  PubMed  Google Scholar 

  62. Perakyla M, Malinen M, Herzig KH, Carlberg C. Gene regulatory potential of nonsteroidal vitamin D receptor ligands. Mol Endocrinol. 2005;19(8):2060–73.

    Article  PubMed  CAS  Google Scholar 

  63. Ciesielski F, Sato Y, Chebaro Y, Moras D, Dejaegere A, Rochel N. Structural basis for the accommodation of bis- and tris-aromatic derivatives in vitamin D nuclear receptor. J Med Chem. 2012;55(19):8440–9.

    Article  CAS  PubMed  Google Scholar 

  64. Gogoi P, Seoane S, Sigueiro R, Guiberteau T, Maestro MA, Perez-Fernandez R, et al. Aromatic-based design of highly active and noncalcemic vitamin D receptor agonists. J Med Chem. 2018;61(11):4928–37.

    Article  CAS  PubMed  Google Scholar 

  65. Chen F, Su Q, Torrent M, Wei N, Peekhaus N, Mcmasters D, et al. Identification and characterization of a novel nonsecosteroidal vitamin D receptor ligand. DrugDev Res. 2007;68(2):51–60.

    Article  CAS  Google Scholar 

  66. Haussler MR, Haussler CA, Bartik L, Whitfield GK, Hsieh JC, Slater S, et al. Vitamin D receptor: molecular signaling and actions of nutritional ligands in disease prevention. Nutr Rev. 2008;66(10 Suppl 2):S98–112.

    Article  PubMed  Google Scholar 

  67. Makishima M, Lu TT, Xie W, Whitfield GK, Domoto H, Evans RM, et al. Vitamin D receptor as an intestinal bile acid sensor. Science. 2002;296:1313–6.

    Article  CAS  PubMed  Google Scholar 

  68. Adachi R, Honma Y, Masuno H, Kawana K, Shimomura I, Yamada S, et al. Selective activation of vitamin D receptor by lithocholic acid acetate, a bile acid derivative. J Lipid Res. 2005;46(1):46–57.

    Article  CAS  PubMed  Google Scholar 

  69. Ishizawa M, Matsunawa M, Adachi R, Uno S, Ikeda K, Masuno H, et al. Lithocholic acid derivatives act as selective vitamin D receptor modulators without inducing hypercalcemia. J Lipid Res. 2008;49(4):763–72.

    Article  CAS  PubMed  Google Scholar 

  70. Masuno H, Kazui Y, Tanatani A, Fujii S, Kawachi E, Ikura T, et al. Development of novel lithocholic acid derivatives as vitamin D receptor agonists. Bioorg Med Chem. 2019;27(16):3674–81.

    Article  CAS  PubMed  Google Scholar 

  71. Arichi N, Fujiwara S, Ishizawa M, Makishima M, Hua DH, Yamada KI, et al. Synthesis and biological evaluation of steroidal derivatives bearing a small ring as vitamin D receptor agonists. Bioorg Med Chem Lett. 2017;27(15):3408–11.

    Article  CAS  PubMed  Google Scholar 

  72. Norman AW, Manchand PS, Uskokovic MR, Okamura WH, Takeuchi JA, Bishop JE, et al. Characterization of a novel analogue of 1alpha,25(OH)(2)-vitamin D(3) with two side chains: interaction with its nuclear receptor and cellular actions. J Med Chem. 2000;43(14):2719–30.

    Article  CAS  PubMed  Google Scholar 

  73. Mizwicki MT, Keidel D, Bula CM, Bishop JE, Zanello LP, Wurtz JM, et al. Identification of an alternative ligand-binding pocket in the nuclear vitamin D receptor and its functional importance in 1alpha,25(OH)2-vitamin D3 signaling. Proc Natl Acad Sci U S A. 2004;101(35):12876–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ciesielski F, Rochel N, Moras D. Adaptability of the Vitamin D nuclear receptor to the synthetic ligand Gemini: remodelling the LBP with one side chain rotation. J Steroid Biochem Mol Biol. 2007;103(3–5):235–42.

    Article  CAS  PubMed  Google Scholar 

  75. Huet T, Maehr H, Lee HJ, Uskokovic MR, Suh N, Moras D, et al. Structure-function study of gemini derivatives with two different side chains at C-20, Gemini-0072 and Gemini-0097. MedChemComm. 2011;2(5):424–9.

    Article  CAS  PubMed  Google Scholar 

  76. Teske KA, Yu O, Arnold LA. Inhibitors for the vitamin D receptor-coregulator interaction. Vitam Horm. 2016;100:45–82.

    Article  PubMed  CAS  Google Scholar 

  77. Ishizuka S, Yamaguchi H, Yamada S, Nakayama K, Takayama H. Stereochemistry of 25-hydroxyvitamin D3-26,23-lactone and 1 alpha, 25-dihydroxyvitamin D3-26,23-lactone in rat serum. FEBS Lett. 1981;134(2):207–11.

    Article  CAS  PubMed  Google Scholar 

  78. Miura D, Manabe K, Ozono K, Saito M, Gao Q, Norman AW, et al. Antagonistic action of novel 1alpha,25-dihydroxyvitamin D3-26, 23-lactone analogs on differentiation of human leukemia cells (HL-60) induced by 1alpha,25-dihydroxyvitamin D3. J Biol Chem. 1999;274(23):16392–9.

    Article  CAS  PubMed  Google Scholar 

  79. Kakuda S, Ishizuka S, Eguchi H, Mizwicki MT, Norman AW, Takimoto-Kamimura M. Structural basis of the histidine-mediated vitamin D receptor agonistic and antagonistic mechanisms of (23S)-25-dehydro-1alpha-hydroxyvitamin D3-26,23-lactone. Acta Crystallogr D Biol Crystallogr. 2010;66(Pt 8):918–26.

    Article  CAS  PubMed  Google Scholar 

  80. Saito N, Saito H, Anzai M, Yoshida A, Fujishima T, Takenouchi K, et al. Dramatic enhancement of antagonistic activity on vitamin D receptor: a double functionalization of 1alpha-hydroxyvitamin D3 26,23-lactones. Org Lett. 2003;5(25):4859–62.

    Article  CAS  PubMed  Google Scholar 

  81. Saito N, Matsunaga T, Saito H, Anzai M, Takenouchi K, Miura D, et al. Further synthetic and biological studies on vitamin D hormone antagonists based on C24-alkylation and C2alpha-functionalization of 25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactones. J Med Chem. 2006;49(24):7063–75.

    Article  CAS  PubMed  Google Scholar 

  82. Bury Y, Steinmeyer A, Carlberg C. Structure activity relationship of carboxylic ester antagonists of the vitamin D(3) receptor. Mol Pharmacol. 2000;58(5):1067–74.

    Article  CAS  PubMed  Google Scholar 

  83. Zugel U, Steinmeyer A, Giesen C, Asadullah K. A novel immunosuppressive 1alpha,25-dihydroxyvitamin D3 analog with reduced hypercalcemic activity. J Invest Dermatol. 2002;119(6):1434–42.

    Article  CAS  PubMed  Google Scholar 

  84. Kato Y, Nakano Y, Sano H, Tanatani A, Kobayashi H, Shimazawa R, et al. Synthesis of 1alpha,25-dihydroxyvitamin D3-26,23-lactams (DLAMs), a novel series of 1 alpha,25-dihydroxyvitamin D3 antagonist. Bioorg Med Chem Lett. 2004;14(10):2579–83.

    CAS  PubMed  Google Scholar 

  85. Nakano Y, Kato Y, Imai K, Ochiai E, Namekawa J, Ishizuka S, et al. Practical synthesis and evaluation of the biological activities of 1 alpha,25-dihydroxyvitamin D-3 antagonists, 1 alpha,25-dihydroxyvitamin D-3-26,23-lactams. Designed on the basis of the helix 12-folding inhibition hypothesis. J Med Chem. 2006;49(8):2398–406.

    Article  CAS  PubMed  Google Scholar 

  86. Cho K, Uneuchi F, Kato-Nakamura Y, Namekawa J, Ishizuka S, Takenouchi K, et al. Structure-activity relationship studies on vitamin D lactam derivatives as vitamin D receptor antagonist. Bioorg Med Chem Lett. 2008;18(15):4287–90.

    Article  CAS  PubMed  Google Scholar 

  87. Lamblin M, Spingarn R, Wang TT, Burger MC, Dabbas B, Moitessier N, et al. An o-aminoanilide analogue of 1alpha,25-dihydroxyvitamin D(3) functions as a strong vitamin D receptor antagonist. J Med Chem. 2010;53(20):7461–5.

    Article  CAS  PubMed  Google Scholar 

  88. Inaba Y, Yamamoto K, Yoshimoto N, Matsunawa M, Uno S, Yamada S, et al. Vitamin D3 derivatives with adamantane or lactone ring side chains are cell type-selective vitamin D receptor modulators. Mol Pharmacol. 2007;71(5):1298–311.

    Article  CAS  PubMed  Google Scholar 

  89. Igarashi M, Yoshimoto N, Yamamoto K, Shimizu M, Ishizawa M, Makishima M, et al. Identification of a highly potent vitamin D receptor antagonist: (25S)-26-adamantyl-25-hydroxy-2-methylene-22,23-didehydro-19,27-dinor-20-epi-vita min D3 (ADMI3). Arch Biochem Biophys. 2007;460(2):240–53.

    Article  CAS  PubMed  Google Scholar 

  90. Kudo T, Ishizawa M, Maekawa K, Nakabayashi M, Watarai Y, Uchida H, et al. Combination of triple bond and adamantane ring on the vitamin D side chain produced partial agonists for vitamin D receptor. J Med Chem. 2014;57(10):4073–87.

    Article  CAS  PubMed  Google Scholar 

  91. Watarai Y, Ishizawa M, Ikura T, Zacconi FC, Uno S, Ito N, et al. Synthesis, biological activities, and X-ray crystal structural analysis of 25-hydroxy-25(or 26)-adamantyl-17-[20(22),23-diynyl]-21-norvitamin D compounds. J Med Chem. 2015;58(24):9510–21.

    Article  CAS  PubMed  Google Scholar 

  92. Inaba Y, Yoshimoto N, Sakamaki Y, Nakabayashi M, Ikura T, Tamamura H, et al. A new class of vitamin D analogues that induce structural rearrangement of the ligand-binding pocket of the receptor. J Med Chem. 2009;52(5):1438–49.

    Article  CAS  PubMed  Google Scholar 

  93. Anami Y, Sakamaki Y, Itoh T, Inaba Y, Nakabayashi M, Ikura T, et al. Fine tuning of agonistic/antagonistic activity for vitamin D receptor by 22-alkyl chain length of ligands: 22S-hexyl compound unexpectedly restored agonistic activity. Bioorg Med Chem. 2015;23(22):7274–81.

    Article  CAS  PubMed  Google Scholar 

  94. Yamamoto K, Inaba Y, Yoshimoto N, Choi M, DeLuca HF, Yamada S. 22-Alkyl-20-epi-1alpha,25-dihydroxyvitamin D3 compounds of superagonistic activity: syntheses, biological activities and interaction with the receptor. J Med Chem. 2007;50(5):932–9.

    Article  CAS  PubMed  Google Scholar 

  95. Nandhikonda P, Yasgar A, Baranowski AM, Sidhu PS, McCallum MM, Pawlak AJ, et al. Peroxisome proliferation-activated receptor delta agonist GW0742 interacts weakly with multiple nuclear receptors, including the vitamin D receptor. Biochemistry. 2013;52(24):4193–203.

    Article  CAS  PubMed  Google Scholar 

  96. Teske K, Nandhikonda P, Bogart JW, Feleke B, Sidhu P, Yuan N, et al. Modulation of transcription mediated by the vitamin D receptor and the peroxisome proliferator-activated receptor delta in the presence of GW0742 analogs. J Biomol Res Ther. 2014;3(1):1000111.

    Google Scholar 

  97. Teske KA, Rai G, Nandhikonda P, Sidhu PS, Feleke B, Simeonov A, et al. Parallel chemistry approach to identify novel nuclear receptor ligands based on the GW0742 scaffold. ACS Comb Sci. 2017;19(10):646–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Teske KA, Bogart JW, Arnold LA. Novel VDR antagonists based on the GW0742 scaffold. Bioorg Med Chem Lett. 2018;28(3):351–4.

    Article  CAS  PubMed  Google Scholar 

  99. Teske K, Nandhikonda P, Bogart JW, Feleke B, Sidhu P, Yuan N, et al. Identification of Vdr antagonists among nuclear receptor ligands using virtual screening. Nucl Recept Res. 2014;1:1–8.

    Article  Google Scholar 

Download references

Acknowledgments

This work was supported by the University of Wisconsin-Milwaukee, the Milwaukee Institute for Drug Discovery, the UWM Research Growth Initiative, NIH R03DA031090, the UWM Research Foundation, the Lynde and Harry Bradley Foundation, and the Richard and Ethel Herzfeld Foundation.

Author information

Authors and Affiliations

  1. Department of Chemistry and Biochemistry and Milwaukee Institute for Drug Discovery (MIDD), University of Wisconsin, Milwaukee, WI, USA

    Tania R. Mutchie, Daniel A. Webb, Elliot S. Di Milo & Leggy A. Arnold

Authors
  1. Tania R. Mutchie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel A. Webb
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elliot S. Di Milo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leggy A. Arnold
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leggy A. Arnold .

Editor information

Editors and Affiliations

  1. School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA

    Mostafa Z. Badr

Rights and permissions

Reprints and permissions

Copyright information

© 2021 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Mutchie, T.R., Webb, D.A., Di Milo, E.S., Arnold, L.A. (2021). Strategies for the Design of Vitamin D Receptor Ligands. In: Badr, M.Z. (eds) Nuclear Receptors. Springer, Cham. https://doi.org/10.1007/978-3-030-78315-0_8

Download citation

Publish with us

Policies and ethics

Search

Navigation