MK-3134
MK-3134 is an orally active, brain-penetrant and selective histamine H3 receptor inverse agonist. MK-3134 modulates histaminergic neurotransmission, decreases constitutive H3 receptor signaling, releases tonic inhibition of neurotransmitter release, potentiates neurotransmission, and may enhance cholinergic neurotransmission. MK-3134 can be used for the research of Alzheimer's disease.
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- No. CAS: 862310-66-5
- Fòrmula: C25H26F3N3O2
- Peso molecular:457.49
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Almacenamiento:
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Actividad biológica
Descripciòn
IC50 & Target
[4]|
H3 receptor 3.6 nM (Ki) |
Cellular Effect
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| CHO-K1 | IC50 |
0.33 nM
Compound: 5s
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Antagonist activity at human cloned histamine H3 receptor expressed in CHO-K1 cells assessed as inhibition of R-alpha-methylhistamine-induced [35S]GTPgammaS binding
Antagonist activity at human cloned histamine H3 receptor expressed in CHO-K1 cells assessed as inhibition of R-alpha-methylhistamine-induced [35S]GTPgammaS binding
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[PMID: 18841880] |
In Vitro
MK-3134 (Compound 5s) exhibits an IC50 of 0.33 nM against human H3[5].
MK-3134 (below 1 μM) is a highly selective nanomolar-affinity ligand for histamine H3 receptors, with no meaningful off-target activity at other histamine receptor subtypes or additional tested targets at concentrations below 1 μM[2].
MK-3134 binds to the human histamine H3 receptor with a Ki of 3.6 nM[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
Parmacokinetics
| Species | Dose | Route | CL | AUC0-∞ | Cmax | F |
|---|---|---|---|---|---|---|
| Rat[5] | 1 mg/kg | i.v. | 24 mL/min/kg | / | / | / |
| Rat[5] | 3 mg/kg | p.o. | / | 1.66 μM·h | 0.42 μM | 33 % |
| Dog[5] | 0.3 mg/kg | i.v. | 13 mL/min/kg | / | / | / |
| Dog[5] | 1 mg/kg | p.o. | / | 1.3 μM·h | 0.28 μM | 46 % |
| Rhesus monkey[5] | 0.3 mg/kg | i.v. | 26 mL/min/kg | / | / | / |
| Rhesus monkey[5] | 1 mg/kg | p.o. | / | 0.15 μM·h | 0.05 μM | 11 % |
In Vivo
MK-3134's (0.3-3 mg/kg; p.o.; single dose) brain penetration is significantly influenced by P-gp in mice model[5].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:SD rats (male)[5]
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Dosage:1 mg/kg; 3 mg/kg; 10 mg/kg
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Administration:p.o.; single dose
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Result:Significantly and dose-proportionally elevated tele-methylhistamine in the male SD rats brain.
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Animal Model:mdr1a (+/+) and mdr1a (−/−) CF-1 mice (female)[5]
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Dosage:0.3 mg/kg; 1 mg/kg; 3 mg/kg
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Administration:p.o.; single dose
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Result:Significantly elevated brain penetration in mdr1a (−/−) CF-1 mice, with about 5-fold higher than those in mdr1a (+/+) CF-1 mice.
Ensayo clínico
| NCT Number | Sponsor | Condition | Start Date |
Phase
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|---|---|---|---|---|
| NCT01329991 | 2011-05 | PHASE1 |
Chemical Information
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No. CAS 862310-66-5
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Peso molecular 457.49
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Fòrmula C25H26F3N3O2
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SMILES
O=C1C2=C(C=CC=C2C(F)(F)F)N=C(C)N1C3=CC=C(C=C3)OC4CCN(C5CCC5)CC4
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Referencias
[1]. Cho W, et al. Additive effects of a cholinesterase inhibitor and a histamine inverse agonist on scopolamine deficits in humans. Psychopharmacology (Berl). 2011;218(3):513-524. [Content Brief]
[2]. Van Laere KJ, et al. (11)C-MK-8278 PET as a tool for pharmacodynamic brain occupancy of histamine 3 receptor inverse agonists. J Nucl Med. 2014 Jan;55(1):65-72. [Content Brief]
[3]. Jończyk J, et al. Search for multifunctional agents against Alzheimer's disease among non-imidazole histamine H3 receptor ligands. In vitro and in vivo pharmacological evaluation and computational studies of piperazine derivatives. Bioorg Chem. 2019;90:103084. [Content Brief]
[4]. Łażewska D, et al. Cholinesterase inhibitory activity of chlorophenoxy derivatives-Histamine H3 receptor ligands. Bioorg Med Chem Lett. 2016;26(16):4140-4145. [Content Brief]
[5]. Nagase T, et al. Synthesis and evaluation of structurally constrained quinazolinone derivatives as potent and selective histamine H3 receptor inverse agonists. J Med Chem. 2008 Nov 13;51(21):6889-901. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
MK-3134 Related Classifications
HY-182581 Related Classifications
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