palovarotene
palovarotene Basic information
- Product Name:
- palovarotene
- Synonyms:
-
- palovarotene
- 4-[(1E)-2-[5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-3-(1H-pyrazol-1-ylmethyl)-2-naphthalenyl]ethenyl]benzoic acid
- Unii-28K6I5m16g
- R 667
- Ro 3300074
- (E)-4-(2-(3-((1H-pyrazol-1-yl)Methyl)-5,5,8,8-tetraMethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)benzoic acid
- Palovarotene(R 667)
- R 667;RO 3300074
- CAS:
- 410528-02-8
- MF:
- C27H30N2O2
- MW:
- 414.54
- EINECS:
- 200-258-5
- Mol File:
- 410528-02-8.mol
palovarotene Chemical Properties
- Melting point:
- 249-252°C
- Boiling point:
- 592.3±50.0 °C(Predicted)
- Density
- 1.11
- storage temp.
- Refrigerator
- solubility
- DMSO (Slightly), Ethyl Acetate (Slightly, Heated), Methanol (Slightly, Heated)
- pka
- 4.26±0.10(Predicted)
- form
- Solid
- color
- White to Off-White
- InChIKey
- YTFHCXIPDIHOIA-DHZHZOJOSA-N
- SMILES
- C(O)(=O)C1=CC=C(/C=C/C2=C(CN3C=CC=N3)C=C3C(=C2)C(C)(C)CCC3(C)C)C=C1
palovarotene Usage And Synthesis
Description
Palovarotene an orally bioavailable retinoic acid receptor γ (RARγ) agonist. It increases retinoic acid response element (RARE) activity and decreases NF-κB activity induced by IL-1β in primary mouse stromal cells in reporter assays when used at a concentration of 60 nM. Palovarotene (10 nM) inhibits activin A-induced chondrogenic and osteogenic differentiation of mouse fibro/adipogenic progenitors (FAPs) expressing a mutated form of human activin A receptor type I (ACVR1R206H). It inhibits heterotopic ossification and preserves limb movement and growth in a ACVR1R206H fibrodysplasia ossificans progressiva (FOP) mouse model. Palovarotene (1 mg/kg per day for 14 days) decreases heterotopic ossification by 50 to 60% in a rat model of traumatic blast injury.
Uses
Palovarotene, is a highly selective retinoic acid receptor gamma (RAR-γ) agonist that is under investigation as a potential treatment for emphysema.
Definition
ChEBI: Palovarotene is a stilbenoid.
in vivo
Palovarotene suppresses post-traumatic chondrogenesis and osteogenesis and mitigated trauma-induced ectopic bone formation. Palovarotene inhibits subcutaneous and intramuscular heterotopic ossification (HO) in mice. Palovarotene is given orally for 14 days at 1 mg/kg/day starting on post-operative day (POD) 1 or POD-5, and HO amount, wound dehiscence and related processes are monitored for up to 84 days post injury. Compared to vehicle-control animals, Palovarotene significantly decreases HO by 50 to 60% regardless of when the treatment started and if infection is present[1]. Starting from day 1 of injury, half of the Acvr1cR206H/+ mice are treated with Palovarotene by daily gavage for 14 days and the other half received vehicle as control. Analysis by mCT and 3D image reconstruction at day 14 shows that large HO tissue masses have formed in the targeted leg of Acvr1cR206H/+ mutant mice receiving vehicle, but HO formation is greatly diminished in Palovarotene-treated companions by more than 80% based on bone volume/total volume quantification[2].
References
[1] MATTHEW HIND S S. Palovarotene, a novel retinoic acid receptor gamma agonist for the treatment of emphysema.[J]. Current opinion in investigational drugs, 2009, 10 11: 1243-1250.
[2] SAYANTANI SINHA. Effectiveness and mode of action of a combination therapy for heterotopic ossification with a retinoid agonist and an anti-inflammatory agent[J]. Bone, 2016, 90: Pages 59-68. DOI: 10.1016/j.bone.2016.02.008
[3] JOHN B LEES-SHEPARD. Palovarotene reduces heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity.[J]. eLife, 2018. DOI: 10.7554/elife.40814
[4] SALIN A CHAKKALAKAL. Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1R206H Fibrodysplasia Ossificans Progressiva (FOP) Mutation[J]. Journal of Bone and Mineral Research, 2016, 31 9: 1666-1675. DOI: 10.1002/jbmr.2820
[5] GABRIEL J. PAVEY . Targeted stimulation of retinoic acid receptor-γ mitigates the formation of heterotopic ossification in an established blast-related traumatic injury model[J]. Bone, 2016, 90: Pages 159-167. DOI: 10.1016/j.bone.2016.06.014
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