Topics in Current Chemistry

, 377:28 | Cite as

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

  • Shiyang Zhou
  • Huiying Zou
  • Guangying Chen
  • Gangliang HuangEmail author


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.


Rheumatoid arthritis Chemical drugs Synthesis Biological activities 



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.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Majithia V, Geraci SA (2007) Rheumatoid arthritis: diagnosis and management. Am J Med 120(11):936–939PubMedGoogle Scholar
  2. 2.
    Smolen JS, Aletaha D et al (2016) Rheumatoid arthritis. Lancet 388(10055):2023–2038PubMedGoogle Scholar
  3. 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):1–26Google Scholar
  4. 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):CD008794Google Scholar
  5. 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):571–586PubMedGoogle Scholar
  6. 6.
    Derksen V, Huizinga T, Van D (2017) The role of autoantibodies in the pathophysiology of rheumatoid arthritis. Semin Immunopathol 39(4):437–446PubMedPubMedCentralGoogle Scholar
  7. 7.
    Gao Q, Wang Y, Xu D et al (2018) Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res 6:15Google Scholar
  8. 8.
    Alamanos Y, Drosos AA (2005) Epidemiology of adult rheumatoid arthritis. Autoimmun Rev 4(3):130–136PubMedGoogle Scholar
  9. 9.
    Bottini N, Firestein G (2013) Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat Rev Rheumatol 9(1):24–33PubMedGoogle Scholar
  10. 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):118–128PubMedGoogle Scholar
  11. 11.
    Gaffo A, Saag KG, Curtis JR (2006) Treatment of rheumatoid arthritis. Am J Health Syst Pharm 63(24):2451–2465PubMedGoogle Scholar
  12. 12.
    Oliveira R, Fierro I (2018) New strategies for patenting biological medicines used in rheumatoid arthritis treatment. Expert Opin Ther Pat 28(8):635–646PubMedGoogle Scholar
  13. 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):1530–1536PubMedGoogle Scholar
  14. 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 205:1–7PubMedGoogle Scholar
  15. 15.
    Ichikawa N, Yamanaka H (2012) Disease-modifying antirheumatic drugs. Clin Calcium 22(2):215–221PubMedGoogle Scholar
  16. 16.
    Raoof R, Willemen H, Eijkelkamp N (2018) Divergent roles of immune cells and their mediators in pain. Rheumatology (Oxford) 57(3):429–440Google Scholar
  17. 17.
    Ling S, Bluett J, Barton A (2018) Prediction of response to methotrexate in rheumatoid arthritis. Expert Rev Clin Immunol 14(5):419–429PubMedGoogle Scholar
  18. 18.
    Fox R, Herrmann M, Frangou C et al (1999) Mechanism of action for leflunomide in rheumatoid arthritis. Clin Immunol 93(3):198–208PubMedGoogle Scholar
  19. 19.
    Plosker G, Croom K (2005) Sulfasalazine: a review of its use in the management of rheumatoid arthritis. Drugs 65(13):1825–1849PubMedGoogle Scholar
  20. 20.
    Walker K, Farrow S (2007) Rheumatoid arthritis. BMJ Clin Evid 8:1124–1169Google Scholar
  21. 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):1168–1174PubMedPubMedCentralGoogle Scholar
  22. 22.
    Kirwan J, Bijlsma J, Boers M et al (2007) Effects of glucocorticoids on radiological progression in rheumatoid arthritis. Cochrane Database Syst Rev (1):CD006356Google Scholar
  23. 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):1147–1160PubMedGoogle Scholar
  24. 24.
    Sharma J, Bhar S, Devi C (2017) A review on interleukins: the key manipulators in rheumatoid arthritis. Mod Rheumatol 27(5):723–746PubMedGoogle Scholar
  25. 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 106:1011–1023PubMedGoogle Scholar
  26. 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 126:70–78PubMedGoogle Scholar
  27. 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:j1909PubMedPubMedCentralGoogle Scholar
  28. 28.
    Buer J (2014) Origins and impact of the term ‘NSAID'. Inflammopharmacology 22(5):263–267PubMedGoogle Scholar
  29. 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):1269–1278PubMedGoogle Scholar
  30. 30.
    Derry S, Conaghan P, Da S et al (2016) Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev 4:CD007400PubMedGoogle Scholar
  31. 31.
    Mallinson T (2017) A review of ketorolac as a prehospital analgesic. J Paramed Pract 9(12):522–526Google Scholar
  32. 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):CD008659Google Scholar
  33. 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):CD008392Google Scholar
  34. 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:CD012537PubMedGoogle Scholar
  35. 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:CD012563PubMedGoogle Scholar
  36. 36.
    StarSurg C (2017) Safety of nonsteroidal anti-inflammatory drugs in major gastrointestinal surgery: a prospective, multicenter cohort study. World J Surg 41(1):47–55Google Scholar
  37. 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):66PubMedPubMedCentralGoogle Scholar
  38. 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:j1909PubMedPubMedCentralGoogle Scholar
  39. 39.
    Auriel E, Regev K, Korczyn A (2014) Nonsteroidal anti-inflammatory drugs exposure and the central nervous system. Handb Clin Neurol 119:577–584PubMedGoogle Scholar
  40. 40.
    Fowler C (2017) The contribution of cyclooxygenase-2 to endocannabinoid metabolism and action. Br J Pharmacol 152(5):594–601Google Scholar
  41. 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):139–147Google Scholar
  42. 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):312–320PubMedPubMedCentralGoogle Scholar
  43. 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):385–396PubMedGoogle Scholar
  44. 44.
    Banti C (2016) Non-steroidal anti-inflammatory drugs (NSAIDs) in metal complexes and their effect at the cellular level. Eur J Inorg Chem 19:3048–3071Google Scholar
  45. 45.
    Häggström M, Richfield D (2014) Diagram of the pathways of human steroidogenesis. WikiJ Med 1(1):5Google Scholar
  46. 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):e15607PubMedPubMedCentralGoogle Scholar
  47. 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):203–209PubMedGoogle Scholar
  48. 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 90:17–20PubMedGoogle Scholar
  49. 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):CD010756Google Scholar
  50. 50.
    Chowdhury R, Naaseri S, Lee J et al (2014) Imaging and management of greater trochanteric pain syndrome. Postgrad Med J 90(1068):576–581PubMedGoogle Scholar
  51. 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):232–243PubMedGoogle Scholar
  52. 52.
    Banuelos J, Shin S, Cao Y et al (2016) BCL-2 protects human and mouse Th17 cells from glucocorticoid-induced apoptosis. Allergy 71:640–650PubMedPubMedCentralGoogle Scholar
  53. 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.e10Google Scholar
  54. 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):244–246PubMedGoogle Scholar
  55. 55.
    Buer J (2015) A history of the term DMARD. Inflammopharmacology 23(4):163–171PubMedPubMedCentralGoogle Scholar
  56. 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):3–5PubMedGoogle Scholar
  57. 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):251–256PubMedGoogle Scholar
  58. 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):481–485Google Scholar
  59. 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):4453–4458PubMedGoogle Scholar
  60. 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):1691–1698PubMedPubMedCentralGoogle Scholar
  61. 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 101:326–333PubMedGoogle Scholar
  62. 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 26:5218–5221Google Scholar
  63. 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 60:1159–1170Google Scholar
  64. 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:e1700194Google Scholar
  65. 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):1193–1211Google Scholar
  66. 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 61:4961–4977Google Scholar
  67. 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 26:1495–1510Google Scholar
  68. 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 26:4971–4983Google Scholar
  69. 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 26:4375–4381Google Scholar
  70. 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):2376–2386Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Shiyang Zhou
    • 1
    • 2
  • Huiying Zou
    • 1
    • 2
  • Guangying Chen
    • 1
    • 2
  • Gangliang Huang
    • 3
    Email author
  1. 1.College of Chemistry and Chemical EngineeringHainan Normal UniversityHaikouChina
  2. 2.Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of EducationHainan Normal UniversityHaikouChina
  3. 3.Chongqing Key Laboratory of Green Synthesis and Application, Active Carbohydrate Research InstituteChongqing Normal UniversityChongqingChina

Personalised recommendations