ADVANCEMENTS IN TARGETED THERAPIES FOR RHEUMATOID ARTHRITIS: A COMPARATIVE REVIEW OF CONVENTIONAL AND BIOLOGICAL DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS

ADVANCEMENTS IN TARGETED THERAPIES FOR RHEUMATOID ARTHRITIS: A COMPARATIVE REVIEW OF CONVENTIONAL AND BIOLOGICAL DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS

H. Dhakne, S. P. Bait, A. M. Kasim and A. S. Gurjar *

Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Principal K. M. Kundnani College of Pharmacy, 23 Jote Joy, R. S. Marg, Cuffe Parade, Mumbai, Maharashtra, India.

ABSTRACT: Rheumatoid arthritis (RA) is an autoimmune disease that causes progressive joint damage and systemic complications, leading to significant physical and socioeconomic impacts. Conventional treatments such as nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs) often fail to halt disease progression and prevent cartilage erosion. The review compares conventional therapies with emerging biological DMARDs (bDMARDs) and explores novel therapeutic targets. The advent of bDMARDs in targeting key inflammatory cytokines, such as Janus kinase (JAK), Tumour Necrosis Factor-alpha (TNF-α), and Bruton’s Tyrosine Kinase (BTK), have significantly improved clinical outcomes. Promising agents such as JAK inhibitors (Tofacitinib, Baricitinib), TNF-α blockers (Adalimumab, Etanercept), and BTK inhibitors are under clinical trials, highlighting the potential of targeted therapies in immune modulation. Most of the compounds possess a heterocycle, especially pyridine scaffold, emphasizing the importance of heterocycle to potentiate drug-receptor interaction. Additionally, this paper mentions the rise of innovative therapies, such as Mesenchymal Stem Cell (MSC) therapy, the DEN-181 immune modulation vaccine, and vagus nerve stimulation devices, which focus on tissue regeneration and novel immune pathways. The explored scaffolds, structure-activity relationships, and pharmacological evaluation of small molecule inhibitors and biologics will provide insights for the design of new chemical entities for potential and plausible RA targets. This comprehensive review emphasizes the paradigm shift towards precision medicine, offering a roadmap for integrating combination therapies and novel immunomodulatory approaches for holistic RA management.

Keywords: Rheumatoid arthritis (RA), DMARDs, JAK, TNF-α, BTK

INTRODUCTION: Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that leads to gradual articular and periarticular damage involving several joints in a symmetric pattern. It also causes inflammation, variations in joint integrity and destruction of synovial joints, subchondral bones, tendons and ligaments ¹.

The occurrence of RA in middle-aged females have been observed two to three times greater than in men. A positive family history increases the risk of rheumatoid arthritis roughly three to five times ². Overall, RA is associated with disability, systemic complications along with socioeconomic costs ³.

Approximately worldwide, 18 million people were affected by rheumatoid arthritis in 2020, a significant increase from 1990, when the figure stood at around 12 million ⁴. About 70% of the population suffering from rheumatoid arthritis are women, and 55% of them are older than 55 years. 13 million RA patients experienced severity levels (moderate or severe) that could benefit from rehabilitation ^{4, 5}. Globally, the number of rheumatoid arthritis cases is expected to increase by 40% by 2050, aligned with the aging global population and shifting risk factors. The projected increase in India aligns with global trends, with the number of patients expected to exceed 6.5 million by 2050 ⁶. Despite the availability of many antirheumatic drugs, this disease is still not well managed in up to 30% of RA patients ^{6, 7}. These factors necessitate the need to explore drugs in this therapeutic area.

Pathogenesis and Targets Involved: During the disease progression, leucocytes penetrate the synovial membrane and inflammatory cytokines enter the synovial fluid. This causes long-lasting synovitis which in turn produces autoantibody and furthermore, decreased reactive antigen species boosts pro-inflammatory mediators thus, precipitating the condition. In the pathogenesis pathway, fibroblast-like synoviocytes (FLSs) interact with innate immune system cells (mast cells, dendritic cells, and monocytes/macrophages) and adaptive immune system cells (T-lymphocytes and B-cells) in the pathogenesis pathway, which triggers the inflammatory process Fig. 1.

FIG. 1: ROLE OF NUMEROUS CELLS AND THEIR CYTOKINES IN THE PROGRESSION OF RA ⁸

These two immune systems are closely involved in the development of an important diagnostic marker for RA, anti-citrullinated protein antibodies (ACPA) that enhances the NF-kB pathway and TNF-α which activates inflammatory responses ⁸. Further, the targets involved in the pathogenesis of RA, are discussed here. An influx of Ca²⁺ excites T-cell proliferation and IL2 (interleukin) production, and causes an increase in pro-inflammatory cytokines (IL1, IL6, and TNF-α) levels ⁹. Spleen adherent cells (SAC) causes the inhibition of pro-inflammatory chemokines and cytokines production ¹⁰. cPLA2 represents a central enzyme synthesized at the inflammation site and is a mediator of many inflammatory processes ¹¹. Prostanoid receptor EP2 is stimulated by PGE2 and is a biological target for anti-inflammatory therapy ¹². Therapeutic targets for Th17-(CD4+ T helper (Th) cells, which are essential effectors of the immune response and play a critical role in inflammation-related autoimmune disorders like RA, include receptor-related orphan receptor-gamma-t (RORγt) ^{7, 13}. Protein kinase C theta (PKCθ) has therapeutic potential for T cell-mediated RA and a significant role in T cell signalling ¹⁴. Another intriguing therapeutic target for the management of inflammatory diseases in TNF-mediated inflammation is receptor interacting protein 1 (RIP1) kinase ¹⁵. The release of pro-inflammatory cytokines, TNF and IL, is regulated by the p38 mitogen-activated protein (MAP) kinase ¹⁶. A crucial process in lipid peroxidation is the generation of free radicals which are directly associated in numerous diseases such as atherosclerosis, rheumatoid arthritis ¹⁷. Drug development process has been greatly aided by knowledge about the pathophysiology and the mode of action of these particular immune-targeted therapies. They have identified the immunological pathways responsible for comorbidities and articular inflammation ⁸.

Therapies Available to Treat RA: The current strategies for treatment and management of RA are nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids and disease-modifying antirheumatic drugs (DMARDs) Fig. 2 and 3. Conventional synthetic DMARDs (csDMARDs) include methotrexate (MTX), sulfasalazine, and leflunomide ¹¹. The remission rate is higher when corticosteroids have been administered with a csDMARD (usually MTX), than alone (44.8% to 76.7% for combination therapy and 27.8% to 33.3% for MTX monotherapy) ^{7, 8}. Despite the success of csDMARDs still there are some setbacks. It was claimed by Doan et al. that hepatotoxic effects were associated with the combination therapy of leflunomide with methotrexate than treatment with either drug alone ¹⁸. Conventional drugs exert their onset after several weeks (such as MTX) or months (such as gold salts) ¹⁹. The active metabolite malononitrile amide A77 1726 of the prodrug, leflunomide increases the risk of teratogenic effects ²⁰.

FIG. 2: CONVENTIONAL THERAPIES FOR RA ^20-22

These setbacks forced the researchers to search for new therapeutic approaches and biological DMARDs are one of them. Current tools of molecular and cell biology which have been recognized as promising molecules are the biological DMARDs, which can be targeted for RA treatment. The biological DMARDs target many inflammatory cytokines like TNF-α (Tumour necrosis factor-α), JAK (Janus Kinase), BTK (Bruton Tyrosine Kinase), Interleukins (IL) and have proven to be the most effective treatments over conventional DMARDs. In the past year, the development of effective biologics and small-molecule kinase have shown better clinical results for RA ²³. This mini-review focuses on the molecules which are established, under pipeline and in clinical studies for JAK, TNF-α and BTK inhibitors. It will provide an overview of structural and chemical strategies for designing and developing lead potent molecules.

FIG. 3: CONVENTIONAL DMARDS ^20-22

Biological DMARDs and Their Importance: At present there are nine different biologic therapies available viz, seven are inhibitors of pro-inflammatory cytokines (five targets tumour necrosis factor [TNF], one targets interleukin IL1 and one targets IL6), also agents that target T- and B-lymphocyte. All of these medications are first- or second-line approved therapies in patients who have not reacted to conventional DMARDs, as well as to first-line therapy in many circumstances ²¹. Recombinant biologic molecules that can identify receptors on the cell surface or extracellular molecules with high specificity are called biologic DMARDs (bDMARDs). The bDMARDs are approved as monotherapy in the treatment of RA by the European Medicines Agency (EMA) or United States Food and Drug Administration (FDA). They include the tumour necrosis factor (TNF) inhibitors: certolizumab pegol (CZP, 1998), etanercept (ETN, 1998), infliximab (IFX, 1999), adalimumab (ADA, 2002) ^20-24. When TNF biologic therapy (adalimumab [ADA]) is compared with csDMARDs (MTX) only, the combination treatment led to better response and remission ⁹. A comparative overview of biological treatment over conventional ones gives us a brief insight of their disease-modifying therapeutic potential over symptomatic relief. Hence, we intend to compile information on promising hits and leads explored to inhibit JAK, TNF-α and BTK for RA treatment from a chemist’s point of view.

 Biological Targets:

Janus Kinase (JAK) Inhibition: Small-molecule DMARDs have transformed the RA treatment. Among other tyrosine kinases, the Janus kinases (JAKs) are involved in signal transduction by binding to interleukins (including IL2, IL6, IL12, IL15, etc) receptors ²⁴. Tyrosine kinase family has JAK which comprises a group of four intracellular enzymes viz JAK1, JAK2, JAK3, and TYK2 ^{24, 25}. Type 1 interferon signal transduction is regulated by JAK1. JAK2 interacts with cytokines and other hormones through the glycoprotein-130 subunits. Due to this, JAK2 inhibitor use has been linked to anaemia and thrombocytopenia. Through the common γ chain receptor subunit, JAK3 interacts with many inflammatory cytokines ²⁴. Therefore, it is needed to synthesize a new selective inhibitor against a single JAK isozyme. For the treatment of rheumatoid arthritis, among the four isozymes, JAK1 is important because of its ability to efficiently maintain the cytokines level involved in the disease symptoms than the other JAK ²⁶. Tofacitinib, approved by the US FDA in 2012 which was developed by Pfizer, is thought to work by inhibiting Janus kinases (JAKs). It is a pan-JAK inhibitor that can suppress all JAK isozymes but preferably it inhibits JAK-1 and JAK-2 ²⁷. Synthetic compounds like tofacitinib (TOFA, Compound 1, IC₅₀: 3.1nM) and baricitinib (BARI, Compound 2, IC₅₀: 5.9nM) were mainly synthesised to target the JAKs, are defined as targeted synthetic DMARDs (tsDMARDs) Fig. 4 ⁸. All JAK-1 inhibitor marketed drugs are nitrogen-containing heterocyclic compounds. Compounds 1 and 2 both possess a pyrrolo-pyrimidine ring. Filgotinib (GLPG0634), upadacitinib (ABT-494, Compound 3, IC₅₀ of 0.045 µM), solcitinib (GSK2586184), itacitinib (INCB039110), PF-04965842 are the representative JAK1- selective inhibitors. JAK-3 selective inhibitors are peficitinib and decernotinib Fig. 4 ²⁸. According to Yoshiya Tanaka et al, Peficitinib (Compound 4) is a JAK-3 selective inhibitor for the treatment of RA which is approved in Japan and Korea. Drugs under clinical trials are all JAK-1 inhibitors. Itacitinib (Compound 5) (JAK-1, IC₅₀:10nM) is in phase II clinical trial, Filgotinib Compound 6 under phase III, Solcitinib (Compound 7) and PF-04965842 (Compound 8) clinical trial studies are being conducted by GlaxoSmithKline and Pfizer for evaluating its inflammatory activity. Derocitinib (Compound 9) is also in phase II of its clinical trial. 3(R)-(3-methyl-(7H-pyrrolo[2,3-d] pyrimidin-4-yl) amine) pyrrolidine-3-oxopropanenitrile (compound 10, IC₅₀:3.1nM) and 1H-pyrrolo[2,3-b] pyridine-5-carboxamide (compound 11, IC₅₀: 5.1nM) are candidates under pipeline Fig. 4. Chemical modification of compound 11 led to a large increase in JAK inhibitor activity and metabolic stability in liver microsomes. Compound 10 is a potential analogue with promising selectivity for JAK1 over JAK 2, 3, and TYK2 and has fewer side effects. Its human liver microsomal stability withstands the liver first pass Fig. 5 ²⁹.

FIG. 4: JAK INHIBITORS – MARKETED ^{19-22, 26, 27}

FIG. 5: JAK INHIBITORS – LEADS UNDER PIPELINE ^{26, 27}

In the past decade, many researcher have focused on the development of heterocyclic small molecule inhibitors with different nucleus such as pyridine, pyrimidine, imidazole, indole, pyrazole, pyrrole and triazine ³⁰. Gehringer M. et al have highlighted the development of novel tricyclic compounds targeting JAK3, and achieved good selectivity and activity. By applying the rigidization method, the 3-methyl-1, 6-dihydrodipyrrolo [2, 3-b:2’,3’-d] pyridine scaffold was designed based on the tofacitinib–JAK3 crystal structure ³¹. A series of compounds were synthesized containing the tricyclic structure. Compound 12 was found to be the most potent JAK3 inhibitor with an IC₅₀ value of 220 pM. as compared to tofacitinib, with IC₅₀ values < 3 nM, the lowest concentration evaluated it demonstrated a notable shift in inhibitory efficacy towards STAT5/6 ³¹. In 2017, Kaur M. et al, have synthesized oxindole derivatives for the inhibition of both JAK3 and SYK. Compound 13 was the most active among the synthesized compounds, and showed better in-vivo antiarthritic activity than the standard drug Indomethacin ³².

FIG. 6: REPORTED JAK INHIBITORS ^31-36

He L. et al developed a highly selective JAK3 covalent inhibitor containing purine heterocycle that targeted Cys909 residue in JAK3. Compound 14 exhibited IC₅₀ value of 57 nM demonstrating excellent selectivity. The compound showed potent JAK/STAT inhibition with superior pharmacokinetic properties compared to tofacitinib ³³. The researchers have also synthesized pyrimidine heterocyclic compounds as selective, irreversible covalent JAK3 inhibitors. Compound 15 was found to have the highest selectivity and potency with IC₅₀ value of 0.14 nM and showed significant anti-inflammatory activity in mice models ³⁴. Fensome A. et al described the TYL2 and JAK1-dual inhibitor, containing a constrained piperazinyl-pyrimidine ring. Compound 16 exhibited an excellent off-target polypharmacology and pharmacokinetic profiles consistent with once daily dosing in humans. It showed an IC₅₀ value of 23 nM for TYK2 and 17 nM for JAK1. It inhibited the cytokine pathways relevant to RA³⁵.

Covington. et al synthesized a series of 3(R)-aminopyrrolidine compounds exhibiting JAK-1 selective inhibition. Compound 17, showed improved selectivity for JAK1 compared to that of tofacitinib (IC₅₀ 11, 2.4 x 10², 2.8 x 10³, and 1.1 x 10² nM for JAK1, JAK2, JAK3, and TYK2, respectively) ³⁷. 4-(1H-pyrazol-4-yl)-7H-pyrrolo [2,3-d] pyrimidine derivatives were synthesized in two series by combining different N-acylpiperidine motifs with baricitinib by Jiang F. et al. Compound 18 displayed anti-inflammatory activity by inhibiting LPS-induced NO generation from RAW264.7 macrophages better than reference baricitinib. It exhibited strong inhibition of JAK1 and JAK2 with an IC₅₀ of 88.2 μM ³⁶. Zhou S. et al designed and synthesized 4- or 6-phenyl-pyrimidine derivatives as selective JAK3 inhibitors. Compound 19 showed potent JAK3 inhibition (IC₅₀ = 1.7 nM) with exceptional selectivity over other JAK isoforms (>588-fold for JAK1 and JAK2) (Fig. 6) ³⁷.

TNF-alpha Inhibition: The start and development of RA and other immune-mediated diseases are dependent on a pro- inflammatory cytokine, tumour necrosis factor. The effectiveness of anti-TNF- biological therapies was demonstrated. Since the discovery of anti-TNF- biologics, much effort has been put into creating a tiny, oral TNF- antagonist. Inflammation can be caused by activated monocytes, macrophages, and T lymphocytes. Local bone loss is caused by elevated levels of TNF-α in inflammatory musculoskeletal disorders. TNF receptors 1 and 2 have different species specificity and varied affinities via which TNF-α gets activated. Important signalling pathways, including the NF-κB route, RANKL signalling, the extracellular signal-regulated kinase (ERK) signalling system, the tumour progression locus 2 (TPL2) pathway, and proapoptotic signalling, which can be triggered by the interaction of TNF-α and its receptors ³⁸. Corticosteroids and disease-modifying anti-rheumatic medications (DMARDs) are the traditional treatment options for RA. Biopharmaceuticals, particularly TNF inhibitors, offer improved chances for disease management with stronger anti-arthritic benefits for patients who do not respond well to these drugs ³⁹. Hence, there is a need to design and develop more drugs acting through this mechanism.

The marketed TNF-α inhibitors are Infliximab (compound 20), Adalimumab (compound 21), Etanercept (compound 22) Fig. 7. and Golimumab. H. E. Seymar et al reports usage of Etanercept and Infliximab in the UK to RA patients ⁴⁰. Once a month, infliximab is given. INF biosimilars for infliximab, such as IFXdyyb, SB2, CT-P13, BOW015, NI-071, PF-06438179/GP1111, STI-002, and ABP 710, have been approved by few countries. Some countries have approved biosimilars for Adalimumab (Ada), including ZRC-3197, ABP 501,117 Adfrar, and others. Etanercept was developed by Amgen and Wyeth Pharmaceuticals, the permitted biosimilars for it are SB4 and GP2015. It is given twice a week ^{38, 39}.

The soluble and transmembrane bioactive forms of human TNF-α are both bound by the Human Ig G1 kappa monoclonal antibody golimumab. Once a month, it is given subcutaneously. Two golimumab biosimilars that are presently in the preclinical stage are BOW100 and ONS-3035. Certolizumab, a human anti-TNF-α antibody fragment, neutralizes soluble and membrane-linked TNF-α when it is chemically bound to polyethylene glycol. One certolizumab pegol biosimilar that is presently undergoing preclinical phase testing is called PF-688 ⁴¹.

FIG. 7: TNF-Α INHIBITORS - MARKETED ⁴²

FIG. 8: TNF-Α INHIBITORS – LEADS UNDER PIPELINE ^{41, 42}

The TNF-α converting enzyme (TACE) produces TNF-α, which is a crucial cytokine involved in pathogenesis of RA. TACE is one of the targets to block TNF-α in biological fluid. Marimastat (Compound 23, IC₅₀=3.8 nM), Prinomastat (Compound 24, IC₅₀= 22 nM), CGS-27023A (Compound 25) and GW3333 (Compound 26, IC₅₀: 40nM) drugs are under pipeline to inhibit TACE ⁴². The leads under pipeline such as compound 23, 24, 25 and 26 possess primarily amide and sulfonamide moieties Fig. 8. The development of small-molecule inhibitors for TNF-α involves a multidisciplinary approach that integrates computational and experimental strategies.

A crucial tool in this approach is molecular docking, which makes it possible to virtually screen extensive compound libraries against TNF-α to find possible leads. By predicting binding affinities and interactions within the active site of TNF-α, docking studies provide valuable insights into structure-activity relationships and facilitate the rational design of inhibitors. Advanced e-pharmacophore modelling and binary QSAR methods further enhance the accuracy of virtual screenings, narrowing down the candidates with optimal pharmacokinetic and toxicity profiles. Techniques such as Claisen–Schmidt ^{42, 43} condensation and Algar–Flynn–Oyamada ^{43, 44}reactions have proven instrumental in constructing bioactive scaffolds. These methods allow precise functional group modifications, essential for optimizing anti-inflammatory activity. The iterative feedback between docking simulations and synthetic experiments accelerates the discovery of effective and selective TNF-α inhibitors, ultimately bridging the gap between computational predictions and biological validation. Hatnapure et al. developed a new series of 3-hydroxy-2-(2, 4, 5-trimethoxyphenyl)-4H-chromen-4-one derivatives which were synthesized via Claisen–Schmidt condensation and Algar–Flynn–Oyamada reaction, showing potent TNF-α inhibition. 5 – Fluoro – 3 – hydroxyl – 2 - (2, 4, 5-trimethoxyphenyl)-4H-chromen-4-one (Compound 27) Fig. 9 with 81% TNF-α and 92% IL-6 inhibition at 10 μM was the most promising among all the derivatives. The 5-, 6-, and 7-positions are favourable sites for the higher potency. The compounds in the same series with -F at 5 and 7 positions or both, as well as -CF3 at 6-positions, exhibited the highest TNF-α and IL-6 inhibitory activity, as compared to the presence Cl, Br, CH₃, CN, and NO₂ substituents at the same positions Fig. 9 demonstrated no TNF-α or IL-6 inhibitory activity ⁴². Hilmy et al.​ synthesized Diaryl pyrrolopyrimidine and pyrrolothiazine derivatives as inhibitors of TNF-stimulated gene-14 (TSG-14), with (Compound 28) Fig. 9 exhibiting the highest activity (80% TSG-14 inhibition), thus demonstrating its potential as an anti-inflammatory agent ⁴³.

FIG. 9: REPORTED TNF-Α INHIBITORS ^42-5

A study on new dithioic acid derivatives produced by the reaction of natural acids with thiosemicarbazide was carried out by Deepu et al., demonstrating significant anti-inflammatory activity through specific inhibition of TNF-α. Among the compounds tested, (Compound 23) Fig. 9 exhibited the highest in-vitro and in-vivo inhibition rates of 60.09% and 55.96%, respectively. The author highlighted the potential of these derivatives as effective anti-inflammatory agents by targeting TNF-α, a key cytokine in the inflammatory response ⁴⁵. Pandit et al. reported that the imidazo [1,2-b] pyridazine derivative (Compound 30) Fig. 9 exhibited remarkable potency as a TNF-α production inhibitor, with an IC₅₀= 0.4 μM. This efficacy significantly surpasses that of conventional TNF-α inhibitors such as Rolipram, which requires a concentration of 300 μM to achieve 100% inhibition. Additionally, (Compound 31) Fig. 9 also showed promising activity with an IC₅₀ of 0.9 μM. These findings underscore the potential of imidazo[1,2-b] pyridazines as promising alternatives for treatment of inflammatory diseases, offering enhanced efficacy compared to existing therapeutic options ⁴⁴.

Bollenbach et al. identified compound 4-phenylpyridin-2-yl-guanidine (Compound 32) Fig. 9 as a potent inhibitor of TNF-α overproduction, exhibiting an IC₅₀ of 1.2 µM. In models of acute lung inflammation and neuropathic pain, this compound and its rigid mimetic 2-amino dihydroquinazoline showed strong anti-inflammatory effects, indicating a potential substitute for conventional TNF-α inhibitors like etanercept and infliximab, which have a number of side effects and need to be carefully managed by the patient. The presence of a phenyl ring at position 4 of the pyridine nucleus was essential for the activity of (Compound 32). Shifting the phenyl ring to positions 3, 5, or 6 resulted in inactive compounds, indicating that the para position is crucial for maintaining the desired pharmacological effect ⁴⁶.

Using TNF-α inhibition and caspase-3 tests, Aly et al. produced quinoline-2-one/pyrazole compounds and evaluated their anti-inflammatory properties. The derivative that demonstrated the strongest action against the most susceptible cell lines, leukaemia CCRF-CEM and MOLT-4, was Compound 33 Fig. 9. Its IC₅₀ values were 1.35 µM and 2.42 µM for MOLT-4 and CCRF-CEM, respectively significantly reducing TNF-α levels with superior anti-inflammatory effects compared to the reference compound N-acetylcysteine​ ⁴⁷.

In another study, Xiao et al. identified substituted 4-aminoquinolines and 4-aminonaphthyridines as TNF-α inhibitors by using scaffold hopping and structure-based drug discovery. By consolidating the trimer in an inactive configuration, the most potent compound, Compound 34 Fig. 9, demonstrated an IC₅₀ of 41 nM in the HEK-Blue assay and successfully inhibited TNF-α/TNFR signalling ⁴⁸. When comparing these studies, Compound 33 demonstrated significant antioxidant and anti-inflammatory activities, whereas Compound 27 excelled in disrupting TNF-αsignalling via a novel allosteric mechanism. These findings collectively highlight the versatility of quinoline-based derivatives in modulating TNF-α activity ^{48, 49}. Similarly, Indole-based compounds have been gaining momentum as potential candidates in the treatment of rheumatoid arthritis (RA) because of their ability to target important inflammatory pathways. Indole analogues may have a strong inhibiting effect on tumour necrosis factor-alpha (TNF-α) ^{50, 51}.

A cytokine responsible and active in the progression of RA, and inhibit other pro-inflammatory substances including interleukin-6 (IL-6) and nitric oxide (NO). Thus, not only inhibiting the inflammatory process through these indole structures, joint swelling as well as cartilage loss and also bone loss, which are the classic symptoms of RA, will also be addressed. Their ability to modulate the NF-κB signaling pathway also hints at a potential role in therapy, making the indole derivatives a good scaffold for the development of novel anti-rheumatoid arthritis drugs ⁵⁰.

Singh et al. and Kaur et al. have both focused on rationally designing and synthesizing indole derivatives to target TNF-α, a key cytokine involved in inflammatory and tumour-related pathways. Singh et al. developed conjugates of N-substituted indole and aminophenylmorpholin-3-one, identifying (Compound 35) Fig. 9 as the most potent, with a 71% reduction in TNF-α levels and 53% reduction in IL-6 in microglial cells. It also demonstrated strong inhibition of NO and MMP release, along with preventing NF-κB translocation. Similarly, the synthesized indole-morpholinone hybrids and identified Compound 36 & 37 Fig. 9, which inhibited TNF-α production by 75% at 1 μM and displayed GI₅₀ values as low as 0.15 μM in various tumour cell lines, indicating its dual anti-inflammatory and cytotoxic potential^​​ ⁵¹. Kim et al. conducted a comprehensive study on the design, synthesis, and biological evaluation of 3-substituted-indolin-2-one derivatives Fig. 9, identifying their potential as anti-inflammatory agents. The studies utilize RAW264.7 murine macrophages to assess the biological activity of the synthesized compounds. Among the nineteen synthesized derivatives, 3-(3-hydroxyphenyl)-indolin-2-one (Compound 37) Fig. 9 exhibited the highest anti-inflammatory activity, with an IC₅₀ value demonstrating significant inhibition of nitric oxide production and pro-inflammatory cytokines in a concentration-dependent manner.

This compound effectively suppressed the generation of TNF-α and IL-6, also the mRNA expression of iNOS, indicating its potential as a therapeutic agent for inflammatory diseases ⁵⁰. Thalidomide ^{52, 53}, ibuprofen ⁵⁴, sinomenine  ⁵⁵, and tryptanthrin oxime ⁵⁶, derivatives represent diverse pharmacophores with anti-inflammatory and immunomodulatory properties, targeting key mediators like TNF-α, IL-6, and IL-1β in rheumatoid arthritis (RA). By modulating pathways such as NF-κB, MAPK, and COX, these compounds reduce inflammation and alleviate RA symptoms. Thalidomide acts as an immunomodulator, ibuprofen inhibits prostaglandin synthesis, while sinomenine and tryptanthrin oxime derivatives showcase natural and synthetic pharmacophore diversity. Together, they emphasize the value of multi-pathway targeting in RA management and inspire novel therapeutic development ^50-56.

Bruton’s Tyrosine Kinase (BTK) Inhibition: Bruton's tyrosine kinase (BTK), also known as Bruton's agammaglobulinemia tyrosine kinase, is an important cytoplasmic non-receptor tyrosine kinase that plays a significant role in B cell development, differentiation, and signalling ⁵⁷. BTK is mostly expressed in hematopoietic cells, such as B lymphocytes, mast cells, and myeloid cells. It belongs to the Tec family of kinases, which also contains other kinases including ITK, BMX, and TEC ⁵⁸. Among its various isoforms, BTK-A is the most extensively studied and is characterized by its five distinct protein interaction domains: an N-terminal pleckstrin homology (PH) domain, a Tec homology (TH) domain, and Src homology (SH) domains (SH2 and SH3), along with a C-terminal kinase domain responsible for its enzymatic activity ⁵⁹.

BTK is integral to the B-cell receptor (BCR) signalling pathway; upon BCR engagement with antigens, BTK undergoes phosphorylation by upstream kinases such as Lyn and Syk ^{60, 61}. This activation triggers phospholipase C-gamma (PLCγ), which causes the generation of second messengers that propagate crucial downstream signalling cascades, including those involving NF-κB and Akt pathway ⁶¹.

Given its central role in mediating B cell responses, BTK has emerged as a potential therapeutic target for diseases associated with B cell dysregulation, such as rheumatoid arthritis (RA) ⁶². Initially investigated in the context of haematological malignancies, BTK inhibitors like ibrutinib have demonstrated efficacy in treating various B-cell cancers and are now being explored for their potential benefits in RA management ^57-60.

The inhibition of BTK not only disrupts the survival and activation of autoreactive B cells but also offers a novel approach to modulating the inflammatory processes characteristic of RA. Additionally, BTK's expression in myeloid cells such as macrophages and neutrophils highlights its role in the inflammatory response seen in RA, as these cells contribute to cytokine production that exacerbates joint inflammation ⁵⁹. Research has shown that targeting BTK can effectively reduce disease severity in animal models of RA, indicating its multifaceted role in both B cell and innate immune responses ⁶².

Furthermore, ongoing clinical trials are investigating various selective BTK inhibitors beyond ibrutinib that may offer improved efficacy and safety profiles for RA patients ^{61, 62}. Some of them under pipeline are Compound 39 with 8.2 nM potency based on a FRET (Fluorescence resonance energy transfer) biochemical assay. It showed good potency against BTK at ambient bioscience screening done against more than 100 kinases. Compound 39 also exhibited inhibitory activity against Src family kinases ⁶³.

FIG. 10: BTK INHIBITORS- LEADS UNDER PIPELINE ^63-70

A series of 8-amino-imidazo [1,5-α] pyrazine scaffold (Compound 40) Fig. 10 resulted in several promising analogues with excellent BTK inhibitory activity ⁶¹. G-744 Compound 41 in Fig. 10. in animal studies was found to be highly potent, selective for BTK and metabolically stable with an IC₅₀:0.02nM ⁶⁴. Merck Group, Compound 42 (A18, M2951, IC₅₀:8.9nM) is a lead under phase IIb clinical trials, aimed to treat autoimmune diseases including RA. It has a great kinase selectivity profile and acceptable preclinical pharmacokinetic and pharmacodynamic profile ⁶⁵.

Mostly all the structures consist of amino pyrimidine functionality Fig. 10. Additionally, Fenebrutinib (Compound 43), a second generation non covalent BTK inhibitor with amino pyridine scaffold is under phase II clinical trial. It is highly selective and well tolerated in phase I thereby encountering the issue of insufficient potency ^{66, 67}. BTK, a key RA regulator, is targeted by SOMCL-17-016 (Compound 44), a novel selective BTK inhibitor. In a mouse CIA model, SOMCL-17-016 (6.25–25 mg/kg) reduced arthritis severity and bone damage, outperforming ibrutinib and acalabrutinib. It inhibited B cell activation, RANKL expression, and osteoclast differentiation via RANK-BTK-PLCγ2-NFATc1 signalling. This dual action makes SOMCL-17-016 a promising RA treatment ⁶⁸. Poseltinib (HM71224) (Compound 45), a novel BTK inhibitor, irreversibly inhibits BTK (IC₅₀= 1.95 nM), suppresses cytokine production, and prevents osteoclast formation. In a mouse CIA model, it reduced arthritis severity and joint destruction, showing potential as a therapeutic for rheumatoid arthritis ⁶⁹.

TAS5315 (Compound 46), a Bruton’s tyrosine kinase inhibitor (IC₅₀ = 0.85 nM), suppresses B-cell receptor signalling, macrophage cytokine production, and osteoclast activity. TAS5315 is a promising treatment for rheumatoid arthritis by increasing bone density and decreasing joint pathology in collagen-induced arthritis models ⁷⁰. Overall these chemical characteristics suggest that amino groups at ortho positions of nitrogen-containing heterocyclic scaffolds may be helpful to inhibit BTK associated with RA.

FIG. 11: NOVELBTK INHIBITORS ^68-70

Drugs under Clinical Investigation and Preclinical Trials ^67-131: The above indicated biological targets are being extensively explored by researchers and data for some of the drugs which are under clinical investigation and preclinical trials for the same have been compiled in Table 1.

TABLE 1: DRUGS UNDR CLINICAL INVESTIGATION AND PRECLINICAL TRIALS

Emerging Alternative Therapies for RA: The unique capacity of mesenchymal stem cells (MSCs) to alter the immune system, the stem cell therapy is currently being studied as a potential treatment option for individuals with RA DMARDs on long exposure possess adverse effect of systemic weakening of the immune system^{131, 132}. In a study conducted by Huang et al. in 2019, which involved 64 RA patients, discovered that mesenchymal stem cell therapy is a safe treatment option ¹³³. MSCs are differentiating cells capable of forming cartilage, bone, and adipose tissue. Preclinical studies have also shown a positive result in the ability of MSCs to repair tissues, tissue regeneration and its immunomodulatory effects. They play a significant role in the suppression of the immune system by inhibiting the production of inflammatory cytokines ¹³¹.

MSCs convert T cells into regulatory T cells, or Tregs, which are crucial for preserving tolerance and averting RA. They also result in a decrease in Th17/Th1 cells, a reduction in the immunological response to B cells, an increase in IL-10 release, and an increase in Treg cell formation ¹³⁴. Ongoing research is evaluating mesenchymal stem cells for reducing inflammation, repairing joint damage, and slowing disease progression. Mesenchymal stem cell (MSC) therapy is being explored for its potential to repair damaged joints and reduce inflammation ^131-135. The DEN-181 Vaccine is undergoing the first human trials with an aim to use it to reprogram immune responses in RA patients ¹³⁶. Neurostimulation devices, such as vagus nerve stimulators are under investigation for managing RA by modulating immune system activity. Vagus Nerve Stimulation (VNS) experimental trials for VNS have shown promise in reducing RA symptoms through neurostimulation ^{136, 137}. Monoclonal antibody, Olokizumab is under Phase III trials, its target interleukin-6 (IL-6); superior to placebo and comparable to adalimumab (Humira) in trials ^{138, 139}.

CONCLUSION: The therapeutic landscape for rheumatoid arthritis has evolved significantly, transitioning from conventional DMARDs to more targeted approaches involving biological DMARDs. While TNF-α inhibitors like Etanercept and Infliximab remain the most widely prescribed, the increasing focus on Janus kinase (JAK) and Bruton’s Tyrosine Kinase (BTK) inhibitors highlights a shift toward precision medicine in RA. On structural investigation of the biological DMARDs explored, many of them possess pyrimidine scaffold which exist as fused ring system with different heterocycles such as pyrrole, imidazole, pyrazole, amino substituted pyrimidinering has been linked to rings like aryl, heteroaryl, sulfonamido groups. All the above findings, indicate potential role of pyrimidine scaffold in drug design. Despite the efficacy of these agents, unmet clinical needs persist, especially in those patients who don't react well to current treatments.

Emerging strategies such as mesenchymal stem cell (MSC) therapy offer a novel paradigm by targeting tissue regeneration and immune modulation rather than solely symptom management. Early clinical trials of the DEN-181 vaccine and vagus nerve stimulation devices indicate potential in reshaping immune responses and reducing systemic inflammation in RA. Among biological targets, BTK inhibitors are gaining attention, with promising preclinical and clinical candidates showing high selectivity and potency. The current trajectory suggests a future where combination therapies integrating bDMARDs, stem cell therapies, and novel immunomodulatory approaches could provide a holistic and personalized solution for RA management. Further research and clinical validation are essential to translate these innovations into effective, widely accessible treatments.

ACKNOWLEDGEMENT: None

CONFLICTS OF INTEREST: The Authors declare no conflict of interest.

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     Dhakne H, Bait SP, Kasim AM and Gurjar AS: Advancements in targeted therapies for rheumatoid arthritis: a comparative review of conventional and biological disease-modifying anti-rheumatic drugs. Int J Pharm Sci & Res 2026; 17(1): 13-32. doi: 10.13040/IJPSR.0975-8232.17(1).13-32.

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