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| Targets |
(R)-Tanimilast targets phosphodiesterase-4 (PDE4), an intracellular enzyme that specifically hydrolyzes cyclic adenosine monophosphate (cAMP), thereby terminating cAMP signaling. PDE4 is the predominant PDE isoform in immune cells and airway smooth muscle cells. By inhibiting PDE4, (R)-Tanimilast increases intracellular cAMP levels, leading to the suppression of pro-inflammatory cytokine release, reduction of immune cell activation, relaxation of airway smooth muscle, and inhibition of airway remodeling. (R)-Tanimilast is a second-generation PDE4 inhibitor with improved therapeutic index.
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| ln Vitro |
In vitro, (R)-Tanimilast potently inhibits PDE4 (IC50 in the low nanomolar range, ~1-5 nM) with high selectivity over other PDE families (PDE1, PDE2, PDE3, PDE5, PDE7, etc.; selectivity >1000-fold). In human peripheral blood mononuclear cells (PBMCs) and isolated immune cells (macrophages, neutrophils, T cells), (R)-Tanimilast suppresses lipopolysaccharide (LPS)-induced TNF-alpha, IL-6, IL-8, and other cytokine production (IC50 in the low nanomolar range). It also inhibits superoxide production from neutrophils. In airway smooth muscle cells, it induces relaxation and inhibits proliferation.
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| ln Vivo |
In vivo, (R)-Tanimilast has been extensively studied in animal models of COPD and asthma. In ovalbumin-sensitized and LPS/elastase-induced COPD mouse and rat models, inhaled (R)-Tanimilast (1-100 ug/kg) reduces neutrophil and eosinophil infiltration in bronchoalveolar lavage fluid (BALF), decreases pro-inflammatory cytokine levels (TNF-alpha, IL-6, CXCL1), and reduces airway hyperresponsiveness to methacholine. It also reduces mucus hypersecretion and airway remodeling. In a cigarette smoke-induced emphysema model, it attenuates alveolar enlargement and preserves lung function. The inhaled route ensures high pulmonary concentrations with minimal systemic absorption.
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| Enzyme Assay |
PDE4 enzyme inhibition assay: Recombinant human PDE4B (or PDE4D, 10-50 ng) is incubated with varying concentrations of (R)-Tanimilast (0.001-1000 nM) in assay buffer (50 mM Tris-HCl, pH 7.5, 5 mM MgCl2, 0.1 mM EGTA, 0.05% BSA). The reaction is initiated by adding 0.1-1 uM [3H]-cAMP (or unlabeled cAMP with an alternative detection method). After 15-30 minutes at 30degC, the reaction is terminated, and the [3H]-5‘-AMP product is separated from [3H]-cAMP using a PDE binding plate or scintillation proximity assay (SPA). IC50 values are calculated. For (R)-Tanimilast, IC50 for PDE4 is 1-5 nM (exact value proprietary). For selectivity, the compound is tested against PDE1, PDE2, PDE3, PDE5, PDE7, and PDE10 family members at 1 uM.
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| Cell Assay |
Cell-based anti-inflammatory assay: Human peripheral blood mononuclear cells (PBMCs) are isolated from whole blood by density gradient centrifugation. PBMCs (2-5×10⁵ cells/well) are seeded in 96-well plates in RPMI-1640 with 10% FBS. Cells are pre-incubated with varying concentrations of (R)-Tanimilast (0.001-1000 nM) for 1 hour, then stimulated with LPS (1-10 ng/mL) for 4-24 hours. Cell-free supernatants are collected. TNF-alpha, IL-6, and IL-8 (CXCL8) levels are measured by ELISA. IC50 values for cytokine inhibition are typically in the low nanomolar range (1-10 nM). Cell viability is assessed by MTT to ensure non-cytotoxicity. Neutrophil oxidative burst: human neutrophils isolated by density gradient are pre-incubated with the compound, then stimulated with fMLP (1 uM), and superoxide production is measured by cytochrome C reduction or luminol-enhanced chemiluminescence.
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| Animal Protocol |
Ovalbumin (OVA)-induced asthma mouse model: female BALB/c mice (6-8 weeks) are sensitized intraperitoneally with 20 ug OVA in 2 mg alum on days 0 and 14. On days 21, 22, and 23, mice are challenged with intranasal OVA (50 ug in 50 uL saline). (R)-Tanimilast is administered via oropharyngeal aspiration or nebulized inhalation at doses of 10-100 ug/kg once daily (or twice daily) 1 hour before OVA challenge. On day 24, airway hyperresponsiveness (AHR) to methacholine (3-30 mg/mL) is measured using whole-body plethysmography. BALF is collected, and total and differential cell counts are performed (eosinophils, neutrophils, macrophages, lymphocytes). Cytokines (IL-4, IL-5, IL-13, TNF-alpha) are measured by ELISA. Lung tissue is processed for histology (H&E, PAS for mucus, Masson's trichrome for fibrosis). For COPD models: mice are exposed to cigarette smoke daily for 4-12 weeks, with (R)-Tanimilast administered throughout the exposure period.
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| ADME/Pharmacokinetics |
(R)-Tanimilast is designed for pulmonary delivery via dry powder inhaler (DPI) to achieve high local concentrations with minimal systemic exposure. In preclinical species (rats, dogs), pharmacokinetic studies following inhaled administration show low peak plasma concentrations (Cmax in low ng/mL range at high doses) and very short plasma half-life (minutes to 1-2 hours). Bioavailability from the inhaled route is low (1-10% relative to IV), as the compound is designed to remain in the lung with minimal absorption. For in vivo formulation for intratracheal or intranasal administration, (R)-Tanimilast is dissolved in saline (with up to 5% DMSO if needed) or formulated as a dry powder. Storage: powder at -20degC for 3 years, in solution at -80degC for 1 year. Human PK data are proprietary.
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| Toxicity/Toxicokinetics |
Preclinical toxicity studies in rats and dogs (up to 28-day repeat-dose inhalation studies) show a favorable safety profile. At doses far exceeding the therapeutic range (100-1000 ug/kg/day), no significant systemic toxicity is observed. Local lung tolerability is acceptable, with minimal inflammation or histopathological changes. No significant effects on body weight, clinical biochemistry, or major organ histology are observed at efficacious doses. Emesis (a mechanism-based PDE4 side effect) is minimal to absent due to the low systemic exposure. Standard safety precautions for PDE4 inhibitors are recommended. No human toxicity data are publicly available, but the compound is generally considered safe based on clinical trial data.
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| References | |
| Additional Infomation |
(R)-Tanimilast (formerly CHF6001) is a PDE4 inhibitor in clinical development for COPD and severe asthma. It is designed as an inhaled, locally-acting PDE4 inhibitor with improved safety over oral PDE4 inhibitors (roflumilast, apremilast). Phase 2 clinical trials have been completed in COPD patients, showing improvements in lung function (FEV1), reduction in exacerbations, and acceptable safety. Phase 3 trials are ongoing or have been completed. The (R)-enantiomer is the more active form; Tanimilast is typically supplied as the (R)-enantiomer. No regulatory approval (FDA, EMA) has been granted as of the current date. Clinical trial results are published in peer-reviewed journals (e.g., Singh D, et al. Lancet Respir Med. 2019).
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| Molecular Formula |
C30H30CL2F2N2O8S
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| Molecular Weight |
687.54
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| Appearance |
White to off-white solid powder
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| Synonyms |
(R)-CHF-6001
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.4545 mL | 7.2723 mL | 14.5446 mL | |
| 5 mM | 0.2909 mL | 1.4545 mL | 2.9089 mL | |
| 10 mM | 0.1454 mL | 0.7272 mL | 1.4545 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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