Oveporexton: Molecular Structure

Molecular Structure and Properties#

Oveporexton (TAK-861) is a small molecule orexin receptor 2 (OX2R)-selective agonist, not a traditional peptide. It has a molecular weight of 520.52 Da, with the molecular formula C23H25F5N2O4S and CAS number 2460722-04-5. Despite being listed among peptide therapeutics due to its target (the orexin neuropeptide receptor system), oveporexton is a synthetic small molecule designed for oral bioavailability.

Chemical Structure#

The chemical name of oveporexton is N-{(2S,3R)-4,4-Difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide.

Key structural features:

• Pyrrolidine core: A five-membered nitrogen-containing ring that serves as the central scaffold, bearing two stereocenters (2S,3R configuration) that are critical for receptor binding
• 4,4-Difluoro substitution: Geminal fluorine atoms on the pyrrolidine ring enhance metabolic stability and modulate conformational rigidity
• Trifluoro biphenyl group: A biphenyl moiety bearing three fluorine substituents (at the 2-position of one ring and 3',5'-positions of the other) provides hydrophobic receptor interactions
• Ethanesulfonamide: An N-linked sulfonamide group contributes to hydrogen bonding and receptor selectivity
• 2-Hydroxy-2-methylpropanoyl: An N-acyl cap on the pyrrolidine nitrogen that influences pharmacokinetic properties

Physicochemical Properties#

Oveporexton is a lipophilic small molecule designed for oral administration and efficient blood-brain barrier (BBB) penetration:

• Solubility: Freely soluble in DMSO (100 mg/mL, 192 mM) and ethanol (100 mg/mL); insoluble in water
• Oral bioavailability: Sufficient for oral dosing in clinical trials (specific value not publicly disclosed)
• BBB penetration: Preclinical data demonstrate effective brain exposure, as evidenced by dose-dependent neuronal activation in brain arousal centers
• Storage stability: Stable as powder at -20 degrees C for up to 3 years; in DMSO solution at -80 degrees C for up to 1 year

Pharmacokinetics#

Detailed human pharmacokinetic parameters have not been fully disclosed in the public literature. Key available data:

• Route: Oral administration as tablets
• Dosing frequency: Supports both once-daily and twice-daily regimens, suggesting a half-life compatible with BID dosing
• Phase 2b dosing: 0.5 mg BID, 2 mg BID, 2 mg/5 mg QD, and 7 mg QD were all effective
• Phase 3 dosing: 1 mg BID and 2 mg BID were the primary dose regimens
• CNS penetration: Rapid onset of action indicated by clinical effects observed within days of treatment initiation

Receptor Pharmacology#

Oveporexton is a highly selective OX2R agonist. Its receptor engagement profile has been characterized through multiple functional assays:

• OX2R activation (IP1 assay): EC50 = 1.2 nM
• OX2R activation (Ca2+ mobilization): EC50 = 2.5 nM
• OX2R activation (CREB phosphorylation): EC50 = 3.6 nM
• Beta-arrestin recruitment: EC50 = 30 nM
• ERK1/2 phosphorylation: EC50 = 34 nM
• TMN neuron depolarization: EC50 = 31.7 nM

The approximately 3000-fold selectivity for OX2R over OX1R is a key design feature. OX2R is predominantly expressed in wake-promoting brain regions (tuberomammillary nucleus, locus coeruleus, dorsal raphe), while OX1R is involved in reward, stress, and autonomic functions. Selective OX2R agonism is intended to promote wakefulness while avoiding potential adverse effects from OX1R activation.

Structural Comparison with Related Compounds#

vs. Endogenous Orexin Peptides (Orexin-A and Orexin-B)#

Orexin-A and orexin-B are 33-amino-acid and 28-amino-acid neuropeptides, respectively, that are the natural ligands for OX1R and OX2R. Unlike these large peptides, oveporexton is a small molecule (520 Da) that can be administered orally and cross the BBB. Orexin-B shows natural selectivity for OX2R (approximately 10-fold over OX1R), while oveporexton achieves approximately 3000-fold selectivity.

vs. TAK-994 (Danavorexton)#

TAK-994 was Takeda's first-generation OX2R agonist, which showed efficacy in a Phase 2 proof-of-concept study but was discontinued due to hepatotoxicity. Oveporexton is approximately 10-fold more potent than TAK-994, with a distinct chemical scaffold that avoids the hepatotoxicity liability. No cases of liver injury have been observed with oveporexton in clinical trials.

vs. Suvorexant and Lemborexant (Orexin Receptor Antagonists)#

Suvorexant (Belsomra) and lemborexant (Dayvigo) are dual orexin receptor antagonists (DORAs) used to treat insomnia. They block both OX1R and OX2R to promote sleep. Oveporexton acts in the opposite pharmacological direction, activating OX2R to promote wakefulness. These represent two sides of the orexin system: antagonists for insomnia, agonists for narcolepsy.

Related Reading#

• Oveporexton overview and research guide
• Peptides similar to Oveporexton
• Oveporexton research evidence