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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 [68–104]