Skip to main content
SpringerLink
Log in

Development of NK3R Antagonists with a Degradable Scaffold in the Natural Environment: Synthesis and Application of Fused Piperazine Derivatives for Investigation of Degradable Core Motifs

  • Chapter
  • First Online:
Structure–Activity Relationships for Development of Neurokinin-3 Receptor Antagonists

Part of the book series: Springer Theses ((Springer Theses))

  • 141 Accesses

Abstract

For investigation of decomposable scaffolds for the fezolinetant triazopiperazine core in the natural environment, an efficient method for synthesis of [1,2,4]triazolo[4,3-a]piperazine derivatives was established based on gold(I)-catalyzed domino cyclization of an amidrazone substrate with a terminal alkyne. The amidoxime congeners were also converted into [1,2,4]oxadiazolo[4,5-a]piperazine derivatives in the presence of a gold catalyst.

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 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
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. (a) Hoveyda HR, Fraser GL, Roy M, Dutheuil G, Batt F, Bousmaqui MEl, Korac J, Lenoir F, Lapin A, Blanc S (2015) Discovery and optimization of novel antagonists to the human neurokinin‑3 receptor for the treatment of sex-hormone disorders (Part I). J Med Chem 58:3060–3082. (b) Hoveyda HR, Fraser GL, Dutheuil G, El Bousmaqui M, Korac J, Lenoir F, Lapin A, Noël S (2015) Optimization of novel antagonists to the neurokinin‑3 receptor for the treatment of sex-hormone disorders (Part II). ACS Med Chem Lett 6:736–740

    Google Scholar 

  2. (a) Fraser GL, Hoveyda HR, Clarke IJ, Ramaswamy S, Plant TM, Rose C, Millar RP (2015) The NK3 receptor antagonist ESN364 interrupts pulsatile LH secretion and moderates levels of ovarian hormones throughout the menstrual cycle. Endocrinology 156:4214–4225. (b) Fraser GL, Ramael S, Hoveyda HR, Gheyle L, Combalbert J (2016) The NK3 receptor antagonist ESN364 suppresses sex hormones in men and women. J Clin Endocrinol Metab 101:417–426. (c) Skorupskaite K, George JT, Veldhuis J, Millar RP, Anderson RA (2018) Neurokinin 3 receptor antagonism reveals roles for neurokinin B in the regulation of gonadotropin secretion and hot flashes in postmenopausal women. Neuroendocrinology 106:148–157

    Google Scholar 

  3. Kim D, Wang L, Beconi M, Eiermann GJ, Fisher MH, He H, Hickey GJ, Kowalchick JE, Leiting B, Lyons K, Marsilio F, McCann ME, Patel RA, Petrov A, Scapin G, Patel SB, Roy RS, Wu JK, Wyvratt MJ, Zhang BB, Zhu L, Thornberry NA, Weber AE (2005) (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 48:141–151

    Google Scholar 

  4. (a) Ameriks MK, Ao H, Carruthers NI, Lord B, Ravula S, Rech JC, Savall BM, Wall JL, Wang Q, Bhattacharya A, Letavic MA (2016) Preclinical characterization of substituted 6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one P2X7 receptor antagonists. Bioorg Med Chem Lett 26:257–261. (b) Chrovian CC, Soyode-Johnson A, Ao H, Bacani GM, Carruthers NI, Lord B, Nguyen L, Rech JC, Wang Q, Bhattacharya A, Letavic MA (2016) Novel phenyl-substituted 5,6-dihydro-[1,2,4]triazolo[4,3‑a]pyrazine P2X7 antagonists with robust target engagement in rat brain. ACS Chem Neurosci 7:490–497

    Google Scholar 

  5. Johannes JW, Almeida L, Daly K, Ferguson AD, Grosskurth SE, Guan H, Howard T, Ioannidis S, Kazmirski S, Lamb ML, Larsen NA, Lyne PD, Mikule K, Ogoe C, Peng B, Petteruti P, Read JA, Su N, Sylvester M, Throner S, Wang W, Wang X, Wu J, Ye Q, Yu Y, Zheng X, Scott DA (2015) Discovery of AZ0108, an orally bioavailable phthalazinone PARP inhibitor that blocks centrosome clustering. Bioorg Med Chem Lett 25:5743–5747

    Google Scholar 

  6. (a) Schneider G, Neidhart W, Giller T, Schmid G (1999) “Scaffold-Hopping” by topological pharmacophore search: a contribution to virtual screening. Angew Chem Int Ed 38:2894–2896. (b) Sun H, Tawa G, Wallqvist A (2012) Classification of scaffold-hopping approaches. Drug Discov Today 17:310–324

    Google Scholar 

  7. For recent reviews, see: (a) Corma A, Leyva-Pérez A, Sabater MJ (2011) Gold-catalyzed carbon−heteroatom bond-forming reactions. Chem Rev 111:1657–1712. (b) Rudolph M, Hashmi ASK (2011) Heterocycles from gold catalysis. Chem Commun 47:6536–6544. (c) Ohno H (2013) Gold-Catalyzed Cascade Reactions of Alkynes for Construction of Polycyclic Compounds. Isr J Chem 53:869–882. (d) Pflästerera D, Hashmi ASK (2916) Gold catalysis in total synthesis–recent achievements. Chem Soc Rev 45:1331–1367. (e) Zi W, Toste FD (2016) Recent advances in enantioselective gold catalysis. Chem Soc Rev 45:4567–4589

    Google Scholar 

  8. Dorel R, Echavarren AM (2015) Gold (I)-catalyzed activation of alkynes for the construction of molecular complexity. Chem Rev 115:9028–9072 and the references therein

    Google Scholar 

  9. For a review on transition-metal-catalyzed cycloisomerizations, see: Trost BM, Krische MJ (1998) Transition metal catalyzed cycloisomerizations. Synlett 1998:975–976

    Google Scholar 

  10. Intramolecular hydroamination or hydroalkoxylation of alkynes or alkenes catalyzed by various metals have been investigated; see: (a) Bexrud JA, Beard JD, Leitch DC, Schafer LL (2005) Intramolecular hydroamination of unactived olefins with Ti(NMe2)4 as a precatalyst. Org Lett 7:1959–1962. (b) Zhang J, Yang C, He C (2006) Gold(I)-catalyzed intra- and intermolecular hydroamination of unactivated olefins. J Am Chem Soc 128:1798–1799. (c) Michael FE, Cochran BM (2006) Room temperature palladium-catalyzed intramolecular hydroamination of unactivated alkenes. J Am Chem Soc 128:4246–4247. (d) Komeyama K, Morimoto T, Takaki K (2006) A simple and efficient iron‐catalyzed intramolecular hydroamination of unactivated olefins. Angew Chem Int Ed 45:2938–2941. (e) Stubbert BD, Marks TJ (2007) Constrained geometry organoactinides as versatile catalysts for the intramolecular hydroamination/cyclization of primary and secondary amines having diverse tethered C−C unsaturation. J Am Chem Soc 129:4253–4271. (f) Liu Z, Hartwig JF (2008) Mild, rhodium-catalyzed intramolecular hydroamination of unactivated terminal and internal alkenes with primary and secondary amines. J Am Chem Soc 130:1570–1571. (g) Hesp KD, Stradiotto M (2009) Intramolecular hydroamination of unactivated alkenes with secondary alkyl- and arylamines employing [Ir(COD)Cl]2 as a catalyst precursor. Org Lett 11:1449–1452. (h) Dzudza A, Marks TJ (2009) Efficient intramolecular hydroalkoxylation/cyclization of unactivated alkenols mediated by lanthanide triflate ionic liquids. Org Lett 11:1523–1526. (i) Ohmiya H, Moriya T, Sawamura M (2009) Cu(I)-catalyzed intramolecular hydroamination of unactivated alkenes bearing a primary or secondary amino group in alcoholic solvents. Org Lett 11:2145–2147

    Google Scholar 

  11. (a) Leyva A, Corma A (2009) Reusable gold (I) catalysts with unique regioselectivity for intermolecular hydroamination of alkynes. Adv Synth Catal 351:2876–2886. (b) Patil NT, Kavthe RD, Raut VS, Shinde VS, Sridhar B (2010) Gold- and platinum-catalyzed formal Markownikoff’s double hydroamination of alkynes: a rapid access to tetrahydroquinazolinones and angularly-fused analogues thereof. J Org Chem 75:1277–1280. (c) Patil NT, Mutyala AK, Lakshmi PGVV, Gajula B, Sridhar B, Pottireddygari GR, Rao TP (2010) Au(I)-catalyzed cascade reaction involving formal double hydroamination of alkynes bearing tethered carboxylic groups: an easy access to fused dihydrobenzimidazoles and tetrahydroquinazolines. J Org Chem 75:5963–5975. (d) Patil NT, Lakshimi PGVV, Singh V (2010) AuI-Catalyzed Direct Hydroamination/Hydroarylation and Double Hydroamination of Terminal Alkynes. Eur J Org Chem 24:4719–4731. (e) Ji X, Zhou Y, Wang J, Zhao L, Jiang H, Liu H (2013) Au(I)/Ag(I)-catalyzed cascade approach for the synthesis of benzo[4,5]imidazo[1,2-c]pyrrolo[1,2-a]quinazolinones. J Org Chem 78:4312–4318. (f) Lakshimi PGVV, Patil NT (2014) Synthesis of Tetrazolo[1,5-c]quinazolines via Ph3PAuOTf-Catalyzed Double Hydroamination of Terminal Alkynes. Asian J Chem 26:2971–2973. (g) Grammaikopoulou M, Thysiadis S, Sarli V (2015) Gold-catalyzed spiro-N,O-ketal synthesis. Org Biomol Chem 13:1169–1178

    Google Scholar 

  12. Cyr P, Régnier S, Bechara WS, Charette AB (2015) Rapid access to 3-aminoindazoles from tertiary amides. Org Lett 17:3386–3389

    Google Scholar 

  13. (a) Rhee JU, Krische M (2005) Alkynes as synthetic equivalents to stabilized wittig reagents:  intra- and intermolecular carbonyl olefinations catalyzed by Ag(I), BF3, and HBF4. J Org Lett 7:2493–2495. (b) Anderson LL, Arnold J, Bergman RG (2005) Proton-catalyzed hydroamination and hydroarylation reactions of anilines and alkenes: a dramatic effect of counteranions on reaction efficiency. J Am Chem Soc 127:14542–14543. (c) Li M, Yang T, Dixon DJ (2010) Boronic acid catalyzed ene carbocyclization of acetylenic dicarbonyl compounds. Chem Commun 46:2191–2193. (d) Dang TT, Boeck F, Hintermann L (2011) Hidden Brønsted acid catalysis: pathways of accidental or deliberate generation of triflic acid from metal triflates. J Org Chem 76:9353–9361

    Google Scholar 

  14. Gooßen LJ, Rauhaus JE, Deng G (2005) Ru-Catalyzed Anti-Markovnikov Addition of Amides to Alkynes: A Regio- and Stereoselective Synthesis of Enamides. Angew Chem Int Ed 44:4042–4045

    Google Scholar 

  15. Senger J, Melesina J, Marek M, Romier C, Oehme I, Witt O, Sippl W, Jung M (2016) Synthesis and biological investigation of oxazole hydroxamates as highly selective histone deacetylase 6 (HDAC6) inhibitors. J Med Chem 59:1545–1555

    Google Scholar 

  16. (a) Misu R, Oishi S, Yamada A, Yamamura T, Matsuda F, Yamamoto K, Noguchi T, Ohno H, Okamura H, Ohkura S, Fujii N (2014) Development of novel neurokinin 3 receptor (NK3R) selective agonists with resistance to proteolytic degradation. J Med Chem 57:8646–8651. (b) Misu R, Yamamoto K, Yamada A, Noguchi T, Ohno H, Yamamura T, Okamura H, Matsuda F, Ohkura S, Oishi S, Fujii N (2015) Structure–activity relationship study on senktide for development of novel potent neurokinin-3 receptor selective agonists. MedChemComm 6:469–476. (c) Yamamoto K, Okazaki S, Ohno H, Matsuda F, Ohkura S, Maeda K, Fujii N, Oishi S (2016) Development of novel NK3 receptor antagonists with reduced environmental impact. Bioorg Med Chem 24:3494–3500

    Google Scholar 

  17. Mavunkel BJ, Chakravarty S, Perumattam JJ, Luedtke GR, Liang X, Lim D, Xu Y, Laney M, Liu DY, Schreiner GF, Lewicki A, Dugar S (2003) Indole-based heterocyclic inhibitors of p38α MAP kinase: designing a conformationally restricted analogue. Bioorg Med Chem Lett 13:3087–3090

    Google Scholar 

  18. Glide (2018) Schrödinger release 2018-1. Schrödinger, LLC, New York, NY

    Google Scholar 

  19. MacroModel (2018) Schrödinger release 2018-1. Schrödinger, LLC, New York, NY

    Google Scholar 

  20. Harder E, Damm W, Maple J, Wu C, Reboul M, Xiang JY, Wang L, Lupyan D, Dahlgren MK, Knight JL, Kaus JW, Cerutti DS, Krilov G, Jorgensen WL, Abel R, Friesner RA (2016) OPLS3: a force field providing broad coverage of drug-like small molecules and proteins. J Chem Theory Comput 12:281–296

    Google Scholar 

  21. Hearn KN, Nalder TD, Cox RP, Maynard HD, Bell TDM, Pfeffer FM, Ashton TD (2017) Modular synthesis of 4-aminocarbonyl substituted 1, 8-naphthalimides and application in single molecule fluorescence detection. Chem Commun 53:12298–12301

    Google Scholar 

  22. Aubineau T, Cossy J (2013) Chemoselective alkynylation of N-sulfonylamides versus amides and carbamates–Synthesis of tetrahydropyrazines. Chem Commun 49:3303–3305

    Google Scholar 

  23. Chawla R, Van Puyenbroeck V, Pflug NC, Sama A, Ali R, Schols D, Vermeire K, Bell TW (2016) tuning side arm electronics in unsymmetrical cyclotriazadisulfonamide (CADA) endoplasmic reticulum (ER) translocation inhibitors to improve their human cluster of differentiation 4 (CD4) receptor down-modulating potencies. J Med Chem 59:2633–2647

    Google Scholar 

  24. Kalia D, Pawar SP, Thopate JS (2017) Stable and Rapid Thiol Bioconjugation by Light‐Triggered Thiomaleimide Ring Hydrolysis. Angew Chem Int Ed 56:1885–1889

    Google Scholar 

  25. Qi M, Hülsmann M, Godt A (2016) Spacers for geometrically well-defined water-soluble molecular rulers and their application. J Org Chem 81:2549–2571

    Google Scholar 

  26. Kokkala P, Mpakali A, Mauvais FX, Papakyriakou A, Daskalaki I, Petropoulou I, Kavvalou S, Papathanasopoulou M, Agrotis S, Fonsou TM, van Endert P, Stratikos E, Georgiadis D (2016) Optimization and structure–activity relationships of phosphinic pseudotripeptide inhibitors of aminopeptidases that generate antigenic peptides. J Med Chem 59:9107–9123

    Google Scholar 

  27. Liu S, Wei W, Li Y, Liu X, Cao X, Lei K, Zhou M (2015) Design, synthesis, biological evaluation and molecular docking studies of phenylpropanoid derivatives as potent anti-hepatitis B virus agents. Eur J Med Chem 95:473–482

    Google Scholar 

  28. Baucom KD, Guram AS, Borths CJ (2015) Effective conversion of heteroaromatic ketones into primary amines via hydrogenation of intermediate ketoximes. Synlett 26:201–204

    Google Scholar 

  29. Cambeiro F, López S, Varela JA, Saá C (2014) Vinyl dihydropyrans and dihydrooxazines: cyclizations of catalytic ruthenium carbenes derived from alkynals and alkynones. Angew Chem Int Ed 53:5959–5963

    Google Scholar 

  30. Zhai H, Borzenko A, Lau YY, Ahn SH, Schafer LL (2012) Catalytic asymmetric synthesis of substituted morpholines and piperazines. Angew Chem Int Ed 51:12219–12223

    Google Scholar 

  31. Scott SK, Grenning AJ (2017) An enyne cope rearrangement enables polycycloalkane synthesis from readily available starting materials. Angew Chem Int Ed 56:8125–8129

    Google Scholar 

  32. Yang X, Liu G, Li H, Zhang Y, Song D, Li C, Wang R, Liu B, Liang W, Jing Y, Zhao G (2010) Novel oxadiazole analogues derived from ethacrynic acid: design, synthesis, and structure−activity relationships in inhibiting the activity of glutathione S-transferase P1-1 and cancer cell proliferation. J Med Chem 53:1015–1022

    Google Scholar 

  33. LigPrep (2018) Schrödinger release 2018-1. Schrödinger, LLC, New York, NY

    Google Scholar 

  34. Protein Preparation Wizard (2018) Schrödinger release 2018-1. Schrödinger, LLC, New York, NY

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

    Koki Yamamoto

Authors
  1. Koki Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Koki Yamamoto .

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Yamamoto, K. (2020). Development of NK3R Antagonists with a Degradable Scaffold in the Natural Environment: Synthesis and Application of Fused Piperazine Derivatives for Investigation of Degradable Core Motifs. In: Structure–Activity Relationships for Development of Neurokinin-3 Receptor Antagonists. Springer Theses. Springer, Singapore. https://doi.org/10.1007/978-981-15-2965-8_3

Download citation

Publish with us

Policies and ethics

Search

Navigation