MK-8666
MK-8666 is an orally active selective FFA1 agonist of GPR40 that stimulates glucose-dependent insulin secretion. MK-8666 binds to the allosteric partial agonist site, activates Gq signaling, positively modulates GPR40 in synergy with endogenous free fatty acids, and exhibits functional and ligand-binding cooperativity with AgoPAM as well as induced-fit conformational changes. MK-8666 can be used for research on type 2 diabetes.
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- No. CAS: 1544739-75-4
- Fòrmula: C29H31NO6S
- Peso molecular:521.62
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Almacenamiento:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Actividad biológica
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Chemical Information
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Actividad biológica
Descripciòn
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FFAR1 |
GPR40 |
In Vitro
MK-8666 (10 μM) shows CoA/ATP-dependent covalent binding in rat and human liver microsomes, reaching 27 and 260 pmol equivalents/mg protein, respectively, exceeding UDPGA-dependent binding of 13 and 49 pmol equivalents/mg protein; A1-A3 transacylation adducts are present in both systems, whereas A4a-c glucuronidation adducts appear only in the presence of UDPGA[1].
MK-8666 enhances AM1638-, AP8-, and AP4-stimulated IP1 accumulation in HEK293 cells expressing human GPR40, demonstrating positive functional cooperativity[6].
MK-8666 binds WT and triple-mutant hGPR40 with high affinity in HEK293 whole-cell binding assays and shows positive binding cooperativity with AP8, with approximately four-fold lower binding affinity for the triple mutant than for WT[6].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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 1544739-75-4
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Peso molecular 521.62
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Fòrmula C29H31NO6S
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SMILES
O=C(O)[C@H]1[C@]([H])(CC2=C3C=NC(OCC4=CC(C5=C(C=C(C=C5C)OCCCS(=O)(C)=O)C)=CC=C4)=C2)[C@@]13[H]
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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]. Shang J, et al. Bioactivation of GPR40 Agonist MK-8666: Formation of Protein Adducts in Vitro from Reactive Acyl Glucuronide and Acyl CoA Thioester. Chemical research in toxicology. 2020 Jan 21;33(1):191-201. [Content Brief]
[2]. Lu S, et al. Small Molecule Allosteric Modulators of G‑Protein-Coupled Receptors: Drug–Target Interactions. Journal of medicinal chemistry. 2019 Jan 10;62(1):24-45. [Content Brief]
[4]. Hyde AM, et al. Synthesis of the GPR40 Partial Agonist MK-8666 through a Kinetically Controlled Dynamic Enzymatic Ketone Reduction. Organic letters. 2016 Nov 18;18(22):5888-5891. [Content Brief]
[5]. Krug AW, et al. Leveraging a Clinical Phase Ib Proof-of-Concept Study for the GPR40 Agonist MK-8666 in Patients With Type 2 Diabetes for Model-Informed Phase II Dose Selection. Clinical and translational science. 2017 Sep;10(5):404-411. [Content Brief]
[6]. Lu J, et al. Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40. Nature structural & molecular biology. 2017 Jul;24(7):570-577. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
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