Therapeutic candidates | MW | Primary effects | Structure | Notes on preclinical or clinical use |
---|---|---|---|---|
Alendronate sodium C4H12NaNO7P2 ∙ 3H2O Sigma A4978 10 mM stock in H2O | 325.12 | Bisphosphonate that targets farnesyl pyrophosphate synthase and inhibits osteoclast activity [68] Used as a positive control for bone changes in osteoclast assays and animal trials t½ >10 years |
| Approved for treatment of bone loss in osteoporosis and associated with a reduced prevalence of subchondral bone lesions in knee OA [69] |
Ascomycin (FK520) C43H69NO12 A3835 (Sigma-Aldrich, St. Louis, MO, USA) 10Â mM stock in DMSO | 792 | Analog of FK506 with strong immunosuppressant properties Acts by binding to immunophilins, especially macrophilin-12 Inhibits production of Th1 (interferon and IL-2) and Th2 (IL-4 and IL-10) Inhibits activation of mast cells [70] |
| The related compound, Pimicrolimus, is effective for treating atopic dermatitis and may also be effective for treating the same condition in psoriasis [71] |
BAY-11-7082 C10H9NO2S 196870 (Calbiochem, San Diego, CA, USA) 48 mM stock in DMSO | 207.25 | Bay 11-7082 is an inhibitor of cytokine-induced IκBα phosphorylation (Calbiochem) |
| Not clinically approved |
BMS-345541 C14H17N5 401480 (Calbiochem) 3.9 mM stock in DMSO | 255.3 | Cell-permeable, allosteric site-binding inhibitor of IKK-2 (reported IC50 300 nM) with tenfold higher selectivity for IKK-2 over IKK-1 (IC50 = 4 μM) [72, 73] t½ = 2.2 h |
| Blocks inflammation and joint destruction in murine arthritis model and blocked MMPs in arthritis model [72, 73] Not clinically approved |
Acetyl-11-keto-β-boswellic acid, (Boswellia serrata) 110123 (Calbiochem) 9.75 mM in DMSO | 512.7 | Blocked TNF-stimulated MMP expression and protected against experimental arthritis [74] Binds to and inhibits IKKα and IKKβ to inhibit NF-κB signaling [75] |
| Clinically tested in an Ayurvedic formulation RA-11 (ARTREX, MENDAR; AyurCore, San Jose, CA, USA) with other nutraceuticals [76] |
Clonidine C9H9Cl2N3 ∙ HCl Lot CTM-723 (AAIPharma, Wilmington, NC, USA) 8.69 mM stock (2 mg/ml) | 266.55 | α2-Receptor agonist and antihypertensive agent Possible induction of iNOS through NF-κB [77] t 1/2 = 6–20 h |
| Used clinically to treat hypertension Clinically tested and found to be effective postoperative analgesic for knee arthroscopy [53] |
CORM-2 (tricarbonyldichlororuthenium(II) dimer; CO-releasing molecule) [Ru(CO)3Cl2]2 Aldrich-288144 (Sigma-Aldrich) 10 mM stock in DMSO | 512 | Decreases oxidative stress in chondrocytes Inhibits IL-1β-induced TNF-α and downregulates NOS-2 and mPGES-1, and COX-2 expression Inhibits p65 NF-κB and HIF-1α DNA-binding activity Reduces IκBα phosphorylation [78] Downregulates MMP-1, MMP-3, MMP-10, MMP-13, and ADAMTS-5 in OA chondrocytes [79] |
| Not clinically approved |
Curcumin Diferuloylmethane (Curcuma longa; turmeric) C21H20O6 C1386 (Sigma-Aldrich) 13.5 mM stock in EtOH | 368.4 | Reportedly inhibits both NF-κB activation and osteoclastogenesis induced by RANKL [80] Modulates genes involved in oxidative stress, apoptosis, inflammation, regulation of transcription, DNA replication, and cellular morphogenesis [81] t 1/2 = 10 min intestinal t 1/2 = 30–50 min plasma |
| Nutraceutical in clinical trials for treatment of colitis, colorectal cancer, and early Alzheimer’s disease Ayurvedic therapeutic and component of RA-11 (nutraceutical mixture) tested in clinical trial for OA [76] Reportedly disease-modifying while blocking pain [76] |
Curcumin-14 Curcumin analog EF24 or 3,5-bis(2-flurobenzylidene)piperidin-4-one [82] Synthesized at Medtronic (Minneapolis, MN, USA) 10 mM stock in DMSO | 311 | Reportedly 10 times more potent than curcumin Inhibits NF-κB by inhibiting IκB kinase (IKK) [82] Potent anticarcinogenic activity inducing death of lung, breast, ovarian, and cervical cancer cells [82] |
| Novel monoketone analog of curcumin Not yet tested clinically |
Diacerein C19H12O8 Nutraceutical that is enriched in rhubarb Breaks down to active metabolite rhein D9302 (Sigma-Aldrich) 27.15 mM stock in DMSO | 368.3 | Reportedly reduces IL-1β, caspase-3, inducible nitric oxide synthase (iNOS), and phosphorylation of c-Jun and c-Jun N-terminal kinase (JNK) Enhances expression of TGF-β1 and TGF-β2 [83] Reportedly inhibits osteoclast bone destruction Reportedly increases chondrocyte production of GAGs and collagen in vitro [83, 84] |
| Claimed disease-modifying OA drug that may slow joint space narrowing [85, 86] Reportedly better than NSAIDs for knee and hip OA with a carryover effect after discontinuation [87] ECHODIAH (3-year placebo-controlled trial on hip OA) showed some positive improvement [85, 86] |
Epigallocatechin-3-gallate C22H18O11 324880 (Calbiochem) 11 mM stock in DMSO | 458.4 | Catechin inhibitor of osteoclastogenesis and NF-κB found in green tea [88] Potent antioxidant that may inhibit cartilage degradation by suppressing AGE-mediated activation and the catabolic response in human chondrocytes [89, 90] t 1/2 = 3–5 h |
| Nutraceutical tested in numerous clinical trials for efficacy in several different diseases [91] |
Fluocinolone Acetonide C24H30F2O6 F3132 (Sigma-Aldrich) 50 mM stock in EtOH | 452.5 | Corticosteroid (potent) Blocks IL-1 and TNF production and TNF-induced apoptosis [92] t 1/2 = 1.3 – 1.7 h |
| FDA-approved as sustained-release intraocular implants for the treatment of diabetic macular edema and uveitis [52] |
GM6001 (generic names galardin, ilomostat) C20H28N4O4 364205 (Calbiochem) 5 mM stock in DMSO | 388.5 | Cell-permeable, broad-spectrum inhibitor of matrix metalloproteinases (MMPs) Prevents the release of TNF-α and blocks endotoxin-induced death in mice (per Calbiochem) |
| In clinical testing for eye disease and COPD (Glycomed, San Diego, CA, USA; Arriva Pharmaceuticals, Alameda, CA, USA; Quick-Med Technologies, Gainesville, FL, USA) |
IKK-2 inhibitor IV [5-(p-Fluorophenyl)-2-ureido]thiophene-3-carboxamide (TPCA-1) Positive control for IKK-2-mediated inflammation Calbiochem | 279.3 | Reportedly a potent cell-permeable inhibitor of IKK-2 (IC50 = 18 nM) with selectivity over IKK-1, JNK, and p38MAPK Inhibits TNF-α in human monocytes (IC50 = 0.15–2.5 μM) Blocks IL-8 and IL-6 in synovial fibroblasts (IC50 = 100 nM) [93] Reduced paw edema in rat inflammatory arthritis model (per Calbiochem) (about 100 % at 30 mg/kg) |
| Not clinically approved Efficacy of TPCA-1 was similar to that of etanercept [93] Inhibitor was tested as potential therapeutic for rheumatoid arthritis (e.g., GSK, London, UK) |
NF-κB activation inhibitor IV [resveratrol derivative (E)-2-fluoro-4′-methoxystilbene] 481412 (Calbiochem) | 228.1 | Experimentally used as an anti-inflammatory but not an antioxidant 130-fold more potent than resveratrol at inhibiting NF-κB [94] |
| Not clinically approved |
IKK-2 inhibitor V IMD-0354 N-(3,5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide C15H8ClF6NO2 3.8 mM stock in EtOH 401482 (EMD Millipore, Billerica, MA, USA) | 383.7 | Cell-permeable IKK-2 inhibitor and established inhibitor of NF-κB pathway Reported IC50 = 250 nM for block of IκBα phosphorylation [95] |
| Approved for atopic dermatitis (Institute for Medicinal Molecular Design, Tokyo, Japan) |
IKK-2 inhibitor VI (5-Phenyl-2-ureido)thiophene-3-carboxamide C12H11N3O2S 401483 (Calbiochem) 3.8 mM stock in DMSO | 261.3 | Reported cell-permeable, reversible inhibitor of IKK-2 (IC50 = 13–18 nM) Orally bioavailable |
| Not clinically approved |
IKK-2 inhibitor VIII (ACHP) C21H24N4O2 401487 (Calbiochem) 2 mM stock in DMSO | 364.4 | A cell-permeable piperidinyl-pyridine compound and selective inhibitor of IKK-2 (IC50 = 8.5 and 250 nM for IKK-2 and IKK-1, respectively) Orally bioavailable in both rats and mice and effectively inhibited arachidonic acid–induced swelling in murine model (per Calbiochem) |
| Not clinically approved |
Meloxicam (Mobic; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA) C14H12N3NaO4S2 M3935 (Sigma-Aldrich) 2 mM stock in DMSO (saline for in vivo) | 351.4 | Nonsteroidal anti-inflammatory drug (NSAID) that inhibits prostaglandin synthetase (cyclooxygenase) and prostaglandin synthesis Inhibits NF-κB in activated macrophages [96] t 1/2 = 15–20 h |
| Approved for relief of the symptoms of arthritis, primary dysmenorrhea, and fever and also as an analgesic, especially where there is an inflammatory component |
Pimecrolimus C43H68ClNO11 S5004 (Selleck Chemicals, Houston, TX, USA) 10 mM stock in DMSO | 810.5 | Ascomycin macrolactam derivative Like tacrolimus, a calcineurin inhibitor that inhibits release of inflammatory cytokines [97] t 1/2 = 30–100 h |
| Approved for atopic dermatitis (ELIDEL; Meda Pharma, Luxembourg) |
Resveratrol C14H12O3 554325 (Calbiochem) 50 mM stock in DMSO | 228.2 | Suppresses IL-1β signaling and IL-1β-stimulated apoptosis in osteoarthritis [98] A natural inhibitor of NF-κB [99] t 1/2 = 1–3 h |
| Nutraceutical said to protect against neuronal cell death; interferes with the stages of initiation, promotion, and progression of cancer; normalizes blood glucose levels; and acts as an anti-inflammatory The focus of many clinical trials [100] |
Rhein (diacerein derivative) C15H8O6 R7269 (Sigma-Aldrich) 10 mM stock in DMSO | 284.2 | Anthraquinone-active metabolite of diacerein Reduces proliferation of chondrocytes and synoviocytes; inhibits NF-κB activation in vitro [101] t 1/2 = 4.3 h |
| Orally administered diacerein is completely converted to rhein before reaching the systemic circulation |
SC514 C9H8N2OS2 401479 (Calbiochem) 2 mM stock in DMSO | 224.3 | Selective inhibitor of IKK-2 t 1/2 = 12 min |
| Experimental use only |
Sulfasalazine (Azulfidine; Pfizer, New York, NY, USA) C18H14N4O5S S0883 (Sigma-Aldrich) 200 mM stock in DMSO | 398.4 | NSAID t 1/2 = 5 – 10 h |
| Approved for use in RA and OA Generic |
Sulindac C20H17FO3S S8139 (Sigma-Aldrich) 70 mM stock in DMSO | 356.4 | NSAID t 1/2 = 7.8 h |
| Approved for use in RA and OA Generic |
Tacrolimus (FK506) C44H69NO12 Anhydrous F4679 (Sigma-Aldrich) or Prograf (Astellas Pharma, Tokyo, Japan) for clinical use 12.4 mM stock in EtOH | 804 | Immunosuppressant Blocks TNF-α and IL-1β production [64] May be disease-modifying while blocking pain Blocks calcineurin pathway and bone remodeling in RA [65] t 1/2 = 11.3 h |
| Approved for RA in Japan in 2005 (Astellas Pharma) Approved immunosuppressant in United States (1994) Janus drug-eluting stent (Sorin Biomedica, Milan, Italy) Polymer elution tested in models of uveitis [60] |
Tranilast (N-(3′,4′-dimethoxycinnamoyl)anthranilic acid; brand name Rizaben) C18H17NO5 Calbiochem 616400 2 mM stock in DMSO (1 % sodium bicarbonate in vivo) | 327.3 | Anti-inflammatory and analgesic properties in collagen-induced arthritis (RA model) [34]. Suppresses COX-2 and iNOS expression, reduces PGE2 and iNOS-derived NO production in stimulated macrophages. Diminishes TNF-α and IL-1β production [35]. T1/2 = 7.4 h |
| In testing for restenosis (SmithKline Beecham, London, UK; Nuon Therapeutics, San Mateo, CA, USA) Also used and/or tested in Japan (Kissei Pharmaceutical, Matsumoto, Japan) as an antiallergic, antiasthmatic, ophthalmic agent |
Triamcinolone acetonide C24H31FO6 T6501 or clinical grade (Sigma-Aldrich) 10 mM stock in EtOH | 434.5 | Steroid t 1/2 = 88 min |
| Approved for IA injection in OA |
Triamcinolone hexacetonide C21H27FO6 Aristospan (Sandoz, Princeton, NJ, USA) 37.5 mM stock (20 mg/ml) | 532.7 | Steroid t 1/2 = 88 min |
| Approved for IA injection in OA |
Withaferin A (withanolide) C28H38O6 ALX-350-153 (Axxora, Farmingdale, NY, USA) 2.125 mM in EtOH | 470.6 | Reportedly inhibits NF-κB activation by preventing the TNF-α-induced activation of IKK-β (IKK-2) [102] Blocks osteoclastogenesis of bone remodeling [103] t 1/2 = 1.36 h |
| Medicinal plant derivative (nutraceutical) for RA [104] and other inflammatory disorders, especially in India RA-11 (Ayurvedic therapeutic containing Withaferin A) tested in clinical trial for OA (ARTREX; AyurCore) [76] |