Skip to main content

Table 1 Therapeutic candidates that were screened in vitro

From: Randomized controlled studies on the efficacy of antiarthritic agents in inhibiting cartilage degeneration and pain associated with progression of osteoarthritis in the rat

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)
10 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]
  1. ACHP, 2-amino-6-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-4-(4-piperidinyl)-3-pyridinecarbonitrile; AGE, advanced glycation end product; CORM-2, carbon monoxide-releasing molecule 2; COX-2, cyclooxygenase-2; DMSO, dimethyl sulfoxide; ECHODIAH, Evaluation of the Chondromodulating Effect of Diacerein in Osteoarthritis of the Hip; EGCG, epigallocatechin gallate; FDA, U.S. Food and Drug Administration; FK506, tacrolimus; FK520, ascomycin; GAG, glycosaminoglycan; HIF-1α, hypoxia-inducible factor 1α; IA, intraarticular; IC50, concentration at which the response is reduced by half; IκΒα, inhibitor of nuclear factor κB; IKK, inhibitor of nuclear factor κB kinase; IL, interleukin; iNOS, inducible nitric oxide synthase; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; MW, molecular weight; NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; NSAID, nonsteroidal anti-inflammatory drug; OA, osteoarthritis; PGE, prostaglandin E; RA, rheumatoid arthritis; RANKL, receptor activator of nuclear factor κB ligand; SC514, selective reversible inhibitor of inhibitor of nuclear factor κB kinase 2; t 1/2, half-life; TGF-β, transforming growth factor β; Th, helper T immune response-related cell; TNF-α, tumor necrosis factor α; TPCA-1, 5-(p-fluorophenyl)-2-ureido]thiophene-3-carboxamide
  2. Basic information is provided about the source and structure of the chemical, the stock solution, and previous in vitro and in vivo studies [68104]