IPSU is a selective, orally available and brain penetrant OX2R antagonist with a pKi of 7.85.
Revdofilimab (ABBV-368) is a human IgG1 agonist monoclonal antibody against OX40. Among them, OX40 is a member of the TNF receptor superfamily expressed on activated and memory T cell subsets and T regulatory cells[1].
YNT-185 dihydrochloride is a nonpeptide, selective orexin type-2 receptor (OX2R) agonist, with EC50s of 0.028 and 2.75 μM for OX2R and OX1R, respectively. YNT-185 dihydrochloride ameliorates narcolepsy-cataplexy symptoms in mouse models[1][2].
YNT-185 is a nonpeptide, selective orexin type-2 receptor (OX2R) agonist, with EC50s of 0.028 and 2.75 μM for OX2R and OX1R, respectively. YNT-185 ameliorates narcolepsy-cataplexy symptoms in mouse models[1][2].
ACT-335827 is a selective, orally active, brain-penetrant orexin type 1 receptor antagonist. ACT-33582 acts on OXR1 and OXR2 with IC50 values of 6 nM and 417 nM, respectively. ACT-33582 can be used in studies related to neurological disorders[1].
Orexin B, rat, mouse is an endogenous agonist at Orexin receptor with Kis of 420 and 36 nM for OX1 and OX2, respectively.
Orexin receptor antagonist 4 is potent and selective orexin 2 receptor (OX2R) antagonist with an IC50 of 4.27 nM. Orexin receptor antagonist 4 is 61-fold selective for the OX2R over the OX1R (IC50 of 295 nM) (WO2018206959A1; example 1)[1].
Lemborexant (E-2006) is a dual antagonist of the orexin OX1 and OX2 receptors which is under development for treatment of insomnia.
Filorexant (MK-6096) is an orally bioavailable potent and selective reversible antagonist of OX1 and OX2 receptor(<3 nM in binding).
MK-3697 is an isonicotinamide small molecule, acting as a potent and selective Orexin 2 receptor antagonist with Ki = 0.95 nM.IC50 value: 0.95 nM(Ki)Target: Orexin 2 receptor antagonistMK-3697 is a highly potent, orally bioavailable selective orexin 2 receptor antagonists (2-SORAs) that possess acceptable profiles for clinical development. Herein we report additional SAR studies within the “triaryl” amide 2-SORA series focused on improvements in compound stability in acidic media and time-dependent inhibition of CYP3A4. MK-3697 has improved stability and TDI profiles as well as excellent sleep efficacy across species.
[Ala11,D-Leu15]-Orexin B(human) is a potent and selective orexin-2 receptor (OX2) agonist. [Ala11,D-Leu15]-Orexin B(human) shows a 400-fold selectivity for the OX2 (EC50=0.13 nM) over OX1 (52 nM)[1].
SB-334867 free base is a selective non-peptide orexin OX1 receptor antagonist with a pKb value of 7.2.IC50 value: 7.2 (pKb) [1]Target: orexin OX1 receptor in vitro: SB-334867-A inhibited the orexin-A (10 nM) and orexin-B (100 nM)-induced calcium responses (pK(B)=7.27+/-0.04 and 7.23+/-0.03 respectively, n=8), but had no effect on the UTP (3 microM)-induced calcium response in CHO-OX(1) cells. SB-334867-A (10 microM) also inhibited OX(2) mediated calcium responses (32.7+/-1.9% versus orexin-A) [1].in vivo: Single-unit recordings in anesthetized rats demonstrated the central effects of the selective orexin-1 receptor antagonist SB-334867 (2 mg/kg, intravenous), as it reversed the excitatory effects of orexin-A administration (6 microg, intracerebroventricular) on the activity of locus coeruleus (LC) cells [2]. The ICV injection of SB-334867 alone had no effect on the formalin-induced nociceptive behaviors. Pre-treatment with SB-334867 at a dose of 0.5 nmol significantly attenuated the analgesia induced by morphine (at dose 1.5mg/kg of morphine; interphase and phase 2B and at dose 3mg/kg of morphine just phase 2B of formalin test) [3]. Administered alone, SB-334867 (30 mg/kg, but not lower doses) significantly reduced food intake and most active behaviours (eating, grooming, sniffing, locomotion and rearing), while increasing resting. Pretreatment with SB-334867 dose-dependently blocked these effects of orexin-A, with significant antagonism evident at dose levels (3-10 mg/kg) below those required to produce intrinsic behavioural effects under present test conditions in rats [4].Toxicity: Acute systemic treatment with the selective orexin-1 (OX1R) antagonist SB-334867 reduces food intake in rats, an effect associated with an acceleration in behavioural satiety and unrelated to gross behavioural disruption, alterations in palatability, or toxicity.
Fazamorexant (YZJ-1139) is a potent orexin receptor antagonist. Fazamorexant can be used for insomnia research[1][2].
JNJ-54717793, as a brain penetrant, is an orally active, selective and high affinity orexin-1 receptor (OX1R) antagonist (plasma EC50=85 ng/mL). The Ki values of JNJ-54717793 for hOX1R (human OX1R) and hOX2R are 16 nM and 700 nM, respectively. JNJ-54717793 is a potent compound of anxiety disorders[1][2].
Almorexant Hcl (ACT078573) is a potent and competitive dual orexin 1 receptor (OX1)/orexin 2 receptor (OX2) antagonist with Ki values of 1.3 and 0.17 nM for OX1 and OX2, respectively.
OXA(17-33) is a potent and selective orexin-1 receptor (OX1) agonist. OXA(17-33) shows a ∼23-fold selectivity for the OX1 (EC50=8.29 nM) over OX2 (187 nM)[1].
Seltorexant hydrochloride (JNJ-42847922 hydrochloride) is an orally active, high-affinity, and selective OX2R antagonist (pKi values of 8.0 and 8.1 for human and rat OX2R). Seltorexant hydrochloride crosses the blood-brain barrier and quickly occupies OX2R binding sites in the rat brain[1].
Orexin B, human is an endogenous agonist at Orexin receptor with Kis of 420 and 36 nM for OX1 and OX2, respectively.
Suntinorexton, a heterocyclic compound, is an orexin type 2 receptor agonist extracted from patent WO2019027058A1, page 288[1].
Nemorexant is a potent orexin receptor antagonist extracted from patent WO2015083094A1, compound example 7, has IC50s of 2 nM and 3 nM for Ox1 receptor and Ox2 receptor, respectively.
OX2R-IN-1 is a low cytotoxicity profile OX2R-IN-1 antagonist (a potential OX2R binder) with an IC50 value of 484 μM. OX2R-IN-1 can cross the BBB into the brain with a short half-life[1].
Orexin receptor antagonist 2 (compound 30) is a potent orexin receptor antagonist with pKis of 7.69 and 9.78. Orexin receptor antagonist 2 has the potential for the research of insomnia[1].
Tebideutorexant is a potent orexin receptor antagonist. Tebideutorexant can be used for insomnia research[1].
Efizonerimod alfa is a potent monoclonal antibody OX40 activator. Efizonerimod alfa can be used for cancer research[1].
Hypocretin (70-98), human is a polypeptide that is capable of binding to an orexin receptor OX1R and promotes Apoptosis[1].
Nivasorexant is a potent orexin receptor antagonist[1].
SB-649868 is a potent and selective orally active orexin (OX) 1 and OX2 receptor antagonist (pKi =9.4 and 9.5 at the OX1 and OX2 receptor, respectively).
Seltorexant (JNJ-42847922) is an orally active, high-affinity, and selective OX2R antagonist (pKi values of 8.0 and 8.1 for human and rat OX2R). Seltorexant (JNJ-42847922) crosses the blood-brain barrier and quickly occupies OX2R binding sites in the rat brain[1].
Firazorexton is a potent orexin type 2 receptor (OX2R) agonist (patent WO2019027058A1, example 395)[1].
Almorexant(ACT078573) is a potent and competitive dual orexin 1 receptor (OX1)/orexin 2 receptor (OX2) antagonist with Ki values of 1.3 and 0.17 nM for OX1 and OX2, respectively.IC50 value: 1.3/0.7 nM(OX1/OX2 receptor) [1] [2]Target: Dual OX!/OX2 receptorin vitro: [(3)H]Almorexant bound to a single saturable site on hOX(1) and hOX(2) with high affinity (K(d) of 1.3 and 0.17 nM, respectively. In Schild analyses using the [(3)H]inositol phosphates assay, almorexant acted as a competitive antagonist at hOX(1) and as a noncompetitive-like antagonist at hOX(2). In binding kinetic analyses, [(3)H]almorexant had fast association and dissociation rates at hOX(1), whereas it had a fast association rate and a remarkably slow dissociation rate at hOX(2) [1]. in vivo: During the 12-h dark period after dosing, ALM(Almorexant) exacerbated cataplexy in TG mice and increased nonrapid eye movement sleep with heightened sleep/wake fragmentation in both genotypes. ALM showed greater hypnotic potency in WT mice than in TG mice. The 100 mg/kg dose conferred maximal promotion of cataplexy in TG mice and maximal promotion of REM sleep in WT mice. In TG mice, ALM (30 mg/ kg) paradoxically induced a transient increase in active wakefulness [3]. Almorexant 200 mg showed significantly less 'Drug Liking' than both zolpidem doses (p < 0.01), and almorexant 400 mg had smaller effects than zolpidem 20 mg (p < 0.05), while almorexant 1,000 mg was not different from either zolpidem dose [4].