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Purity: ≥98%
Palovarotene (formerly RO-3300074; R-667; Sohonos) is a novel, potent and highly selective retinoic acid receptor gamma (RAR-γ) agonist that is being investigated as a potential treatment for emphysema. Palovarotene effectively inhibited HO in injury-induced and genetic mouse models of the disease. It additionally prevents spontaneous HO, using a novel conditional-on knock-in mouse line carrying the human ACVR1(R206H) mutation for classic FOP. In addition, palovarotene restored long bone growth, maintained growth plate function, and protected growing mutant neonates when given to lactating mothers. Importantly, palovarotene maintained joint, limb, and body motion, providing clear evidence for its encompassing therapeutic potential as a treatment for FOP. Palovarotene (Sohonos) was approved in 2023 by FDA for treating Fibrodysplasia ossificans progressiva.
| Targets |
Nuclear retinoic acid receptor γ (RAR-γ)
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|---|---|
| ln Vitro |
Palovarotene, a potent RAR-γ agonist, is particularly effective in preventing chondrogenesis and HO in both a genetic model of fibrodysplasia ossificans progressiva (FOP) as well as in an animal model of combat-related HO. Treatment with Palovarotene was found to dampen the systemic inflammatory response including the cytokines IL-6 (p = 0.01), TNF-α (p = 0.001), and IFN-γ (p = 0.03) as well as the local inflammatory response via a 76% reduction in the cellular infiltration at post-operative day (POD)-7 (p = 0.03). Palovarotene decreased osteogenic connective tissue progenitor (CTP-O) colonies by as much as 98% both in vitro (p = 0.04) and in vivo (p = 0.01) [2].
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| ln Vivo |
Palovarotene inhibits trauma-induced ectopic bone development and mediates osteogenesis and post-traumatic bone formation. Palovarotene is used to monitor intraoperative and subcutaneous heterotopic ossification (HO) following trauma. During the first 14 days of the trial, palovarotene was given orally at a dose of 1 mg/kg/day beginning on day 1 or day 5. H2O volume, wound breakdown, and associated processes were periodically observed for up to 84 days. When compared to vehicle animals, palovarotene dramatically lowers H2O by 50% to 60% per dosage [1]. Half of the Acvr1cR206H/+ mice got daily treatment with palovarotene for 14 days starting on the first day of damage, while the other half were given a vehicle as a control. Large tissue masses were seen in the target legs of the vector-acvr1cR206H/+ mutation, according to analysis of mCT and 3D image formation reconstructions after 14 days. However, palovarotene-treated partners showed significantly lower HO, as measured by bone volume/total volume formation, which improved by more than 80%[2].
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| Cell Assay |
Effects of Palovarotene on CTP-O Proliferation In Vitro[2]
Muscle-derived rat mesenchymal stem cells (rMSCs) from the quadriceps muscles of two naïve donor rats (2nd passage) were seeded in triplicate at a density of 1 × 103 cells/well in 6-well plates in normal growth media supplemented with 10% FBS, 100 U/ml penicillin, and 100 μg of Fungizone (Lonza) for 24 h at 37°C in fully humidified 5% CO2 in air atmosphere. For the differentiation study group, normal growth media was changed to osteogenic media and supplemented with varying concentrations of Palovarotene (25, 50, 125 nM) or DMSO (125 nM) with media changes every 3 days. After 7 days, adherent cell colonies were rinsed twice with PBS, fixed with 100% methanol for 5 min at room temperature, air-dried, stained with Crystal violet solution for 5 min, and then rinsed with distilled water to remove residual dye. Colonies with greater than 25 cells/colony were counted using light microscopy by a reader (TAD) that was blinded to the treatment groups. |
| Animal Protocol |
Rat Model for Combat-Related HO[2].
Sixty rats were randomly assigned to one of two treatment groups, Palovarotene or vehicle control (5% DMSO in corn oil), with six time points per group (n = 5 rats/treatment group/time point). Twelve rats were used as naïve controls and not exposed to injury. The 60 rats in the treatment groups were subjected to blast overpressure via a pneumatically driven shock tube (120 ± 7 kPa), femur fracture, soft tissue crush injury, and amputation through the zone of injury. Postoperative pain was managed using sustained-release buprenorphine (1.2 mg/kg) subcutaneously on the day of surgery with repeat dosing after 72-h, if needed, as previously described. Rats received via oral gavage (100 μl) of either Palovarotene (1.0 mg/kg; Atomax Chemicals, Shenzhen, China) or vehicle control every other day for 14 days beginning on POD)-1. Palovarotene purity confirmed greater than 98%. Postoperatively, rats were routinely monitored for signs of pain, weight loss, or wound complications and wounds that exhibited signs of infection or dehiscence were irrigated, débrided, and closed. Early euthanasia was performed if rats demonstrated a failure to thrive, persistent infection, or wound dehiscence after a third débridement. At study endpoint, rats were euthanized with pentobarbital (Fatal Plus; 390 mg/kg intraperitoneally; Patterson Veterinary, Devens, MA). Two rats died on POD-1, one from the 7 day vehicle control group and one from the 7 day Palovarotene group leaving a total of four animals in each of these two groups. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Following oral administration of 20mg once daily in healthy adult subjects, the median Tmax was 4.6 hours, the mean Cmax was 140 ng/mL, and the mean AUC(0-τ) was 942 ng*hr/mL. At steady-state, the mean trough concentration of palovarotene was 3.5 ng/mL. The administration of palovarotene with a high-fat, high-calorie meal resulted in an approximate 40% increase in AUC, an approximate 16% increase in Cmax, and a delay in Tmax by approximately 2 hours when compared to its administration under fasting conditions. Following the administration of a 1mg radiolabeled dose of palovarotene in healthy subjects, approximately 97.1% of the administered radioactivity was recovered in the feces, with only 3.2% recovered in the urine. The mean (SD) apparent volume of distribution (Vd/F) is 237 (± 90.1) L following the administration of a single 20 mg dose with food. The apparent total body clearance of palovarotene is approximately 19.9 L/h. Metabolism / Metabolites Palovarotene undergoes extensive metabolism by CYP3A4 and, to a lesser extent, CYP2C8 and CYP2C19. Five metabolites have been observed in plasma: M1 (6,7-dihydroxy), M2 (6-hydroxy), M3 (7-hydroxy), M4a (6-oxo), and M4b (7-oxo). Following oral administration of palovarotene, the parent drug and its four main metabolites (M2, M3, M4a, and M4b) account for approximately 40% of total plasma exposure. The metabolites of palovarotene are functionally inactive, with M3 and M4b carrying 1.7% and 4.2% of the activity of their parent compound, respectively. Biological Half-Life The mean elimination half-life of palovarotene at steady-state is 8.7 hours. |
| Toxicity/Toxicokinetics |
Protein Binding
The protein binding of palovarotene is 97.9% to 99.6% in vitro. |
| References |
[1]. Pavey GJ, et al. Targeted stimulation of retinoic acid receptor-γ mitigates the formation of heterotopic ossification in an established blast-related traumatic injury model. Bone. 2016 Sep;90:159-67.
[2]. Chakkalakal SA, et al. Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1(R206H) Fibrodysplasia Ossificans Progressiva (FOP) Mutation. J Bone Miner Res. 2016 Sep;31(9):1666-75. [3]. Lees-Shepard JB, et al. Palovarotene reduces heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity. Elife. 2018 Sep 18;7. pii: e40814. [2]. Palovarotene inhibits connective tissue progenitor cell proliferation in a rat model of combat-related heterotopic ossification. J Orthop Res. 2018 Apr;36(4):1135-1144. |
| Additional Infomation |
Pharmacodynamics
Palovarotene exerts its pharmacologic effects by inhibiting the pathway(s) responsible for heterotopic ossification in patients with FOP. It is orally bioavailable and can be administered once daily, with allowances for short-term increases in dosage in the event of a flare-up. As with other retinoids, palovarotene can cause birth defects, and it should not be used by patients who are, or intend to become, pregnant. Palovarotene is contraindicated in patients of childbearing potential unless a number of pregnancy prevention strategies are met (e.g. effective contraception, regular pregnancy testing). Palovarotene may also cause a premature physeal closure in growing children. Physeal growth plates should be monitored every 3 months throughout therapy, or more frequently if evidence of adverse effects on growth are observed. At doses up to 2.5 times the maximum recommended dose, palovarotene does not prolong the QT interval to any clinically relevant extent. Palovarotene binds to retinoic acid receptor gamma (RARγ) with a 10-fold greater affinity compared to retinoic acid receptor alpha or beta. In animal models of Fibrodysplasia Ossificans Progressiva (BMP implant in WT mouse, Q207D mouse model, R206H mouse model), palovarotene decreased heterotopic ossification (HO) in a dose-dependent manner as well as inflammatory and fibroproliferative responses at the sites of injury. Additionally, palovarotene also outperformed corticosteroids in preventing HO, with a dexamethasone treatment of 4.4 mg/kg/day for 4 days demonstrating no clinical efficacy on heterotropic bone volume. |
| Molecular Formula |
C27H30N2O2
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|---|---|
| Molecular Weight |
414.54
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| Exact Mass |
414.23
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| Elemental Analysis |
C, 78.23; H, 7.29; N, 6.76; O, 7.72
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| CAS # |
410528-02-8
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| PubChem CID |
10295295
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| Appearance |
Off-white to yellow solid powder
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| Density |
1.1±0.1 g/cm3
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| Boiling Point |
592.3±50.0 °C at 760 mmHg
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| Flash Point |
312.0±30.1 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.595
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| LogP |
7.63
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
31
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| Complexity |
662
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(O)C1=CC=C(/C=C/C2=C(CN3N=CC=C3)C=C4C(C)(C)CCC(C)(C)C4=C2)C=C1
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| InChi Key |
YTFHCXIPDIHOIA-DHZHZOJOSA-N
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| InChi Code |
InChI=1S/C27H30N2O2/c1-26(2)12-13-27(3,4)24-17-22(18-29-15-5-14-28-29)21(16-23(24)26)11-8-19-6-9-20(10-7-19)25(30)31/h5-11,14-17H,12-13,18H2,1-4H3,(H,30,31)/b11-8+
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| Chemical Name |
4-((1E)-2-(5,5,8,8-Tetramethyl-3-(1H-pyrazol-1-ylmethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)ethenyl)benzoic acid
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| Synonyms |
RO-3300074; R-667; RO 3300074; R 667; RO3300074; R667; Sohonos
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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) |
DMSO : ~25 mg/mL (~60.31 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.03 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (5.02 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4123 mL | 12.0616 mL | 24.1231 mL | |
| 5 mM | 0.4825 mL | 2.4123 mL | 4.8246 mL | |
| 10 mM | 0.2412 mL | 1.2062 mL | 2.4123 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.
 Injury-induced heterotopic ossification inAcvr1cR206H/+mutant mice is inhibited by the RARγ agonist Palovarotene. |
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 Palovarotene preserves long bone growth and growth plate organization inPrrx1-R206Hmice.J Bone Miner Res.2016 Sep;31(9):1666-75. |
 Chondrocyte proliferation and progression are altered inPrrx1-R206Hgrowth plates.J Bone Miner Res.2016 Sep;31(9):1666-75. |
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