LY2955303

Uses

LY 2955303, is a potent and selective retinoic acid receptor gamma (RARγ) antagonist with a Ki of 1.09 nM.

Biological Activity

LY2955303 is a potent and selective RARγ antagonist (Ki = 1.09 nM/RARγ, >1.70 μM/RARα, >2.98 μM/RARβ) th at effectively inhibits RARγ-, but not RARα- or RARβ-, dependent reporter activity upon 15 nM all-trans retinoic acid stimulation in respective HEK293 transfectants (KB = 7.11 nM/RARγ, 1.51 μM/RARβ, 4.44 μM/RARα; 10 nM ATRA for RARβ transfectant). LY2955303 exhibits therapeutic efficacy in a r at model of osteoarthritis-like joint pain (ED50 = 0.72 mg/kg; single p.o. dosage 9 days post OA pain induction by MIA intra-articular injection) with good pharmacokinetic properties, aqueous solubility (>1.0 mg/mL in simulated intestinal fluid), oral availability (F = 26%; 10 mg/kg p.o. over 2 mg/kg i.v.), and no RARα antagonism-associated adverse effects (no testicular degeneration up to 10 mg/kg) seen with BMS-189453 treatment or in RARα-knockout mice.

Synthesis

1. THF (1790 L) was added to the reactor followed by methyl 4-[5-(3,5-di-tert-butylphenyl)-1-[4-(4-methylpiperazine-1-carbonyl)phenyl]pyrazol-3-yl]benzoate (358 g, 0.605 mol) and water (1140 mL), keeping the temperature at 8-12 °C. 2. lithium hydroxide monohydrate (38 g, 0.905 mol) was added one time and the reaction mixture was stirred at 8-12 °C for 16 hours. 3. After completion of the reaction, EtOAc (30 L) was added and the pH of the mixture was adjusted to 5 with 1N HCl. 4. The two phases were separated and the aqueous layer was extracted with EtOAc (2 x 10 L). The organic layers were combined, dried with sodium sulfate, filtered and the solvent was removed under reduced pressure to give a solid product. 5. The crude product was purified by column chromatography using DCM/MeOH (20/1) as eluent to give a light yellow solid. 6. The solid was ground in a solvent mixture of acetonitrile/MTBE (1/3, 4 L) for 1 h. The solid was collected by filtration. 7. The solid was dried under vacuum at 50 °C for 72 h to give 4-(5-(3,5-di-tert-butylphenyl)-1-(4-(4-methylpiperazine-1-carbonyl)phenyl)-1H-pyrazol-3-yl)benzoic acid (264.2 g, 75% yield) as a white solid. lc-es/ms m/z 579 [M + H]+.

in vivo

storage

Store at -20°C

References

[1] Patent: WO2013/66640, 2013, A1. Location in patent: Page/Page column 39
[2] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 14, p. 3274 - 3277