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Synthesis and Biological Activities of Chemical Drugs for the Treatment of Rheumatoid Arthritis

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Abstract

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily affects the joints, with the main clinical manifestations being chronic, symmetrical, and peripheral multi-joint inflammatory lesions. Drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GCs), disease-modifying anti-rheumatic drugs (DMARDs), and biologics play a very important role in the treatment of RA. Of these, the most commonly used are chemical drugs, such as NSAIDs, GCs, and DMARDs. In recent years, a number of new compounds have emerged for the treatment of RA, such as SYK inhibitors, JAK inhibitors, NSAID-CAI drugs, and Syk/PDGFR-α/c-Kit inhibitors. In this review, we summarize the most recently developed anti-RA chemical drugs and discuss the synthesis and biological activities of these various new compounds.

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References

  1. Majithia V, Geraci SA (2007) Rheumatoid arthritis: diagnosis and management. Am J Med 120(11):936–939

    PubMed  Google Scholar 

  2. Smolen JS, Aletaha D et al (2016) Rheumatoid arthritis. Lancet 388(10055):2023–2038

    CAS  PubMed  Google Scholar 

  3. Singh J, Saag K, Bridges S et al (2016) 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 68(1):1–26

    PubMed  Google Scholar 

  4. Singh J, Wells G, Christensen R et al (2011) Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev (2):CD008794

  5. Efthimiou P, Kukar M (2010) Complementary and alternative medicine use in rheumatoid arthritis: proposed mechanism of action and efficacy of commonly used modalities. Rheumatol Int 30(5):571–586

    PubMed  Google Scholar 

  6. Derksen V, Huizinga T, Van D (2017) The role of autoantibodies in the pathophysiology of rheumatoid arthritis. Semin Immunopathol 39(4):437–446

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Gao Q, Wang Y, Xu D et al (2018) Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res 6:15

    Google Scholar 

  8. Alamanos Y, Drosos AA (2005) Epidemiology of adult rheumatoid arthritis. Autoimmun Rev 4(3):130–136

    PubMed  Google Scholar 

  9. Bottini N, Firestein G (2013) Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat Rev Rheumatol 9(1):24–33

    CAS  PubMed  Google Scholar 

  10. Mor A, Abramson S, Pillinger M (2005) The fibroblast-likesynovial cell in rheumatoid arthritis: a key player in inflammation and joint destruction. Clin Immunol 115(2):118–128

    CAS  PubMed  Google Scholar 

  11. Gaffo A, Saag KG, Curtis JR (2006) Treatment of rheumatoid arthritis. Am J Health Syst Pharm 63(24):2451–2465

    CAS  PubMed  Google Scholar 

  12. Oliveira R, Fierro I (2018) New strategies for patenting biological medicines used in rheumatoid arthritis treatment. Expert Opin Ther Pat 28(8):635–646

    CAS  PubMed  Google Scholar 

  13. Singh G, Ramry D, Morfeld D et al (1996) Gastrointestinal tract complications of NSAID treatment in rheumatoid arthritis. A prospective observational cohort study. Arch Intern Med 156(14):1530–1536

    CAS  PubMed  Google Scholar 

  14. Pan T, Cheng T, Jia Y et al (2017) Anti-rheumatoid arthritis effects of traditional Chinese herb couple in adjuvant-induced arthritis in rats. J Ethnopharmacol 205:1–7

    PubMed  Google Scholar 

  15. Ichikawa N, Yamanaka H (2012) Disease-modifying antirheumatic drugs. Clin Calcium 22(2):215–221

    CAS  PubMed  Google Scholar 

  16. Raoof R, Willemen H, Eijkelkamp N (2018) Divergent roles of immune cells and their mediators in pain. Rheumatology (Oxford) 57(3):429–440

    CAS  Google Scholar 

  17. Ling S, Bluett J, Barton A (2018) Prediction of response to methotrexate in rheumatoid arthritis. Expert Rev Clin Immunol 14(5):419–429

    CAS  PubMed  Google Scholar 

  18. Fox R, Herrmann M, Frangou C et al (1999) Mechanism of action for leflunomide in rheumatoid arthritis. Clin Immunol 93(3):198–208

    CAS  PubMed  Google Scholar 

  19. Plosker G, Croom K (2005) Sulfasalazine: a review of its use in the management of rheumatoid arthritis. Drugs 65(13):1825–1849

    CAS  PubMed  Google Scholar 

  20. Walker K, Farrow S (2007) Rheumatoid arthritis. BMJ Clin Evid 8:1124–1169

    Google Scholar 

  21. Miller R, Petereit D, Sloan J et al (2016) N08C9 (Alliance): a phase 3 randomized study of sulfasalazine versus placebo in the prevention of acute diarrhea in patients receiving pelvicradiation therapy. Int J Radiat Oncol Biol Phys 95(4):1168–1174

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kirwan J, Bijlsma J, Boers M et al (2007) Effects of glucocorticoids on radiological progression in rheumatoid arthritis. Cochrane Database Syst Rev (1):CD006356

  23. Ethgen O, De Lemos Esteves F, Bruyere O et al (2013) What do we know about the safety of corticosteroids in rheumatoid arthritis. Curr Med Res Opin 29(9):1147–1160

    CAS  PubMed  Google Scholar 

  24. Sharma J, Bhar S, Devi C (2017) A review on interleukins: the key manipulators in rheumatoid arthritis. Mod Rheumatol 27(5):723–746

    CAS  PubMed  Google Scholar 

  25. Thakur S, Riyaz B, Patil A et al (2018) Novel drug delivery systems for NSAIDs in management of rheumatoid arthritis: an overview. Biomed Pharmacother 106:1011–1023

    CAS  PubMed  Google Scholar 

  26. Wang L, Wang K, Chu X et al (2017) Intra-articular injection of Botulinum toxin A reduces neurogenic inflammation in CFA-induced arthritic rat model. Toxicon 126:70–78

    CAS  PubMed  Google Scholar 

  27. Bally M, Dendukuri N, Rich B et al (2017) Risk of acute myocardial infarction with NSAIDs in real world use: Bayesian meta-analysis of individual patient data. BMJ 357:j1909

    PubMed  PubMed Central  Google Scholar 

  28. Buer J (2014) Origins and impact of the term ‘NSAID'. Inflammopharmacology 22(5):263–267

    CAS  PubMed  Google Scholar 

  29. Machado G, Maher C, Ferreira P et al (2017) Non-steroidal anti-inflammatory drugs for spinal pain: a systematic review and meta-analysis. Ann Rheum Dis 76(7):1269–1278

    CAS  PubMed  Google Scholar 

  30. Derry S, Conaghan P, Da S et al (2016) Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev 4:CD007400

    PubMed  Google Scholar 

  31. Mallinson T (2017) A review of ketorolac as a prehospital analgesic. J Paramed Pract 9(12):522–526

    Google Scholar 

  32. Moore R, Derry S, Aldington D et al (2015) Single dose oral analgesics for acute postoperative pain in adults—an overview of Cochrane reviews. Cochrane Database Syst Rev (9):CD008659

  33. Ashley P, Parekh S, Moles D et al (2016) Preoperative analgesics for additional pain relief in children and adolescents having dental treatment. Cochrane Database Syst Rev (8):CD008392

  34. Eccleston C, Cooper T, Fisher E et al (2017) Non-steroidal anti-inflammatory drugs (NSAIDs) for chronic non-cancer pain in children and adolescents. Cochrane Database Syst Rev 8:CD012537

    PubMed  Google Scholar 

  35. Cooper T, Heathcote L, Anderson B et al (2017) Non-steroidal anti-inflammatory drugs (NSAIDs) for cancer-related pain in children and adolescents. Cochrane Database Syst Rev 7:CD012563

    PubMed  Google Scholar 

  36. StarSurg C (2017) Safety of nonsteroidal anti-inflammatory drugs in major gastrointestinal surgery: a prospective, multicenter cohort study. World J Surg 41(1):47–55

    Google Scholar 

  37. Walsem A, Pandhi S, Nixon R et al (2015) Relative benefit-risk comparing diclofenac to other traditional non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors in patients with osteoarthritis or rheumatoid arthritis: a network meta-analysis. Arthritis Res Ther 17(1):66

    PubMed  PubMed Central  Google Scholar 

  38. Bally M, Dendukuri N, Rich B et al (2017) Risk of acute myocardial infarction with NSAIDs in real world use: Bayesian meta-analysis of individual patient data. BMJ 357:j1909

    PubMed  PubMed Central  Google Scholar 

  39. Auriel E, Regev K, Korczyn A (2014) Nonsteroidal anti-inflammatory drugs exposure and the central nervous system. Handb Clin Neurol 119:577–584

    PubMed  Google Scholar 

  40. Fowler C (2017) The contribution of cyclooxygenase-2 to endocannabinoid metabolism and action. Br J Pharmacol 152(5):594–601

    Google Scholar 

  41. Miguel Á (2015) Non-steroidal anti-inflammatory drugs as a treatment for Alzheimer’s disease: a systematic review and meta-analysis of treatment effect. Drugs Aging 32(2):139–147

    Google Scholar 

  42. Kowalski L, Makowska J (2015) Seven steps to the diagnosis of NSAIDs hypersensitivity: how to apply a new classification in real practice. Allergy Asthma Immunol Res 7(4):312–320

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Wang J (2015) Anti-inflammatory drugs and risk of Alzheimer’s disease: an updated systematic review and meta-analysis. J Alzheimers Dis 44(2):385–396

    PubMed  Google Scholar 

  44. Banti C (2016) Non-steroidal anti-inflammatory drugs (NSAIDs) in metal complexes and their effect at the cellular level. Eur J Inorg Chem 19:3048–3071

    Google Scholar 

  45. Häggström M, Richfield D (2014) Diagram of the pathways of human steroidogenesis. WikiJ Med 1(1):5

    Google Scholar 

  46. Liu C, Guan J, Kang Y et al (2010) Inhibition of dehydration-induced water intake by glucocorticoids is associated with activation of hypothalamic natriuretic peptide receptor-A in rat. PLoS One 5(12):e15607

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Liu C, Chen Y, Kang Y et al (2011) Glucocorticoids improve renal responsiveness to atrial natriuretic peptide by up-regulating natriuretic peptide receptor-A expression in the renal inner medullary collecting duct in decompensated heart failure. J Pharmacol Exp Ther 339(1):203–209

    CAS  PubMed  Google Scholar 

  48. Tarner I, Englbrecht M, Schneider M et al (2012) The role of corticosteroids for pain relief in persistent pain of inflammatory arthritis: a systematic literature review. J Rheumatol Suppl 90:17–20

    CAS  PubMed  Google Scholar 

  49. Haywood A, Good P, Khan S et al (2015) Corticosteroids for the management of cancer-related pain in adults. Cochrane Database Syst Rev (4):CD010756

  50. Chowdhury R, Naaseri S, Lee J et al (2014) Imaging and management of greater trochanteric pain syndrome. Postgrad Med J 90(1068):576–581

    PubMed  Google Scholar 

  51. Mohamadi A, Chan J, Claessen F et al (2017) Corticosteroid injections give small and transient pain relief in rotator cuff tendinosis: a meta-analysis. Clin Orthop Relat Res 475(1):232–243

    PubMed  Google Scholar 

  52. Banuelos J, Shin S, Cao Y et al (2016) BCL-2 protects human and mouse Th17 cells from glucocorticoid-induced apoptosis. Allergy 71:640–650

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Massari F, Mastropasqua F, Iacoviello M et al (2012) The glucocorticoid in acute decompensated heart failure: Dr. Jekyll or Mr. Hyde. Am J Emerg Med 30(3):517.e5–517.e10

    Google Scholar 

  54. Gelber J (2017) CORR insights: corticosteroid injections give small and transient pain relief in rotator cuff tendinosis: a meta-analysis. Clin Orthop Relat Res 475(1):244–246

    PubMed  Google Scholar 

  55. Buer J (2015) A history of the term DMARD. Inflammopharmacology 23(4):163–171

    PubMed  PubMed Central  Google Scholar 

  56. Smolen J, Heijde D, Machold K et al (2014) Proposal for a new nomenclature of disease-modifying antirheumatic drugs. Ann Rheum Dis 73(1):3–5

    CAS  PubMed  Google Scholar 

  57. Nandi P, Kingsley G, Scott D (2008) Disease-modifying antirheumatic drugs other than methotrexate in rheumatoid arthritis and seronegative arthritis. Curr Opin Rheumatol 20(3):251–256

    CAS  PubMed  Google Scholar 

  58. Mohammad S, Clowse M, Eudy A et al (2018) Examination of hydroxychloroquine use and hemolytic anemia in G6PDH-deficient patients. Arthritis Care Res 70(3):481–485

    CAS  Google Scholar 

  59. Harbut M, Vilcheze C, Luo X et al (2015) Auranofin exerts broad-spectrum bactericidal activities by targeting thio-redox homeostasis. Proc Natl Acad Sci USA 112(14):4453–4458

    CAS  PubMed  Google Scholar 

  60. Park S, Lee J, Berek J et al (2014) Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53. Int J Oncol 45(4):1691–1698

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Aggarwal R, Singh G, Kaushik P et al (2015) Molecular docking design and one-pot expeditious synthesis of novel 2,5-diarylpyrazolo[1,5-a] pyrimidin-7-amines as anti-inflammatory agents. Eur J Med Chem 101:326–333

    CAS  PubMed  Google Scholar 

  62. Ligua H, Baoshun Z, You Y et al (2016) Synthesis and anti-inflammatory activity of paeonol analogues in the murine model of complete Freund’s adjuvant induced arthritis. Bioorg Med Chem Lett 26:5218–5221

    Google Scholar 

  63. Silvia B, Lorenzo D, Daniela V et al (2017) Design and synthesis of novel non steroidal anti-inflammatory drugs and carbonic anhydrase inhibitors hybrids (NSAIDs-CAIs) for the treatment of rheumatoid arthritis. J Med Chem 60:1159–1170

    Google Scholar 

  64. Linhong H, Heying P, Tingxuan L et al (2017) Design and synthesis of a highly selective JAK3 inhibitor for the treatment of rheumatoid arthritis. Arch Pharm Chem Life Sci 350:e1700194

    Google Scholar 

  65. Maninder K, Manjinder S, Om S (2017) Oxindole-based SYK and JAK3 dual inhibitors for rheumatoid arthritis: designing, synthesis and biological evaluation. Future Med Chem 9(11):1193–1211

    Google Scholar 

  66. Ozlem A, Lorenzo D, Daniela V et al (2018) Discovery of novel nonsteroidal anti-inflammatory drugs and carbonic anhydrase inhibitors hybrids (NSAIDs-CAIs) for the management of rheumatoid arthritis. J Med Chem 61:4961–4977

    Google Scholar 

  67. Chieyeon C, Misuk J, Sunmin L et al (2018) Development of selective inhibitors for the treatment of rheumatoid arthritis: (R)-3-(3-(Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) pyrrolidin-1-yl)-3- oxopropanenitrile as a JAK1-selective inhibitor. Bioorg Med Chem 26:1495–1510

    Google Scholar 

  68. Hisao H, Yasushi A, Ayako M et al (2018) Discovery and structural characterization of peficitinib (ASP015K) as a novel and potent JAK inhibitor. Bioorg Med Chem 26:4971–4983

    Google Scholar 

  69. Xiaokang L, Yahui H, Junfei C et al (2018) Discovery of novel Syk/PDGFR-α/c-Kit inhibitors as multi-targeting drugs to treat rheumatoid arthritis. Bioorg Med Chem 26:4375–4381

    Google Scholar 

  70. Romero-Estudillo I, Viveros-Ceballos JL, Cazares-Carreño O et al (2019) Synthesis of new α-aminophosphonates: evaluation as antiinflammatory agents and QSAR studies. Bioorg Med Chem 15;27(12):2376–2386

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Acknowledgements

The Project was sponsored by the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (No. 2015-1098). The work was also supported by Chongqing Key Research Project of Basic Science and Frontier Technology (No. cstc2017jcyjBX0012), Foundation Project of Chongqing Normal University (No. 14XYY020), Chongqing General Research Program of Basic Research and Frontier Technology (No. cstc2015jcyjA10054), Chongqing Normal University Postgraduate’s Research and Innovation Project (No. YKC17004), the National Natural Science Foundation (21662012, 41866005), Postgraduate Research and Innovation Project of Hainan Normal University (Hsyx2018-8), and Open Foundation Project of Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education (RDZH2019002), China.

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  1. College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou, 571158, China

    Shiyang Zhou, Huiying Zou & Guangying Chen

  2. Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education, Hainan Normal University, Haikou, 571158, China

    Shiyang Zhou, Huiying Zou & Guangying Chen

  3. Chongqing Key Laboratory of Green Synthesis and Application, Active Carbohydrate Research Institute, Chongqing Normal University, Chongqing, 401331, China

    Gangliang Huang

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Zhou, S., Zou, H., Chen, G. et al. Synthesis and Biological Activities of Chemical Drugs for the Treatment of Rheumatoid Arthritis. Top Curr Chem (Z) 377, 28 (2019). https://doi.org/10.1007/s41061-019-0252-5

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