MK-8666 Tris

• CAT Number: I032404
• CAS Number: 2056254-98-7
• Molecular Formula: C33H42N2O9S
• Molecular Weight: 642.764
• Purity: 98%
• Synonyms: MK-8666 tris salt; MK-8666; MK 8666; MK8666
• Solubility: Soluble in DMSO
• Appearance: Solid powder
• Storage: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
• IUPAC Name: (2S,3S,4R)-8-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-9-azatricyclo[4.4.0.02,4]deca-1(10),6,8-triene-3-carboxylic acid: 2-amino-2-(hydroxymethyl)propane-1,3-diol (1:1)
• InChI: InChI=1S/C29H31NO6S.C4H11NO3/c1-17-10-22(35-8-5-9-37(3,33)34)11-18(2)26(17)20-7-4-6-19(12-20)16-36-25-14-21-13-23-27(24(21)15-30-25)28(23)29(31)32;5-4(1-6,2-7)3-8/h4,6-7,10-12,14-15,23,27-28H,5,8-9,13,16H2,1-3H3,(H,31,32);6-8H,1-3,5H2/t23-,27-,28+;/m1./s1
• InChIKey: IMBNJMBRVNORTO-SQMFDTLJSA-N
• SMILES: O=C([C@@H]1[C@@]2([H])C3=CN=C(OCC4=CC=CC(C5=C(C)C=C(OCCCS(=O)(C)=O)C=C5C)=C4)C=C3C[C@@]12[H])O.OCC(CO)(N)CO

MK-8666 is a partial GPCR (G-protein-coupled receptor) agonist that is coordinated with the action of GPR40. GPR40, also known as free fatty acid (FFA) receptor 1 modulates fatty acid-induced insulin secretion in pancreatic beta cells and in intestinal enteroendocrine cells. Thus, MK-8666 has been investigated for treatment of type 2 diabetes mellitus and has been shown to robustly lower glucose without negative effects.

Reference

1: Hyde AM, Liu Z, Kosjek B, Tan L, Klapars A, Ashley ER, Zhong YL, Alvizo O, Agard NJ, Liu G, Gu X, Yasuda N, Limanto J, Huffman MA, Tschaen DM. Synthesis of the GPR40 Partial Agonist MK-8666 through a Kinetically Controlled Dynamic Enzymatic Ketone Reduction. Org Lett. 2016 Nov 18;18(22):5888-5891. Epub 2016 Nov 1. PubMed PMID: 27802043.
2: Krug AW, Vaddady P, Railkar RA, Musser BJ, Cote J, Ederveen A, Krefetz DG, DeNoia E, Free AL, Morrow L, Chakravarthy MV, Kauh E, Tatosian DA, Kothare PA. 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. Clin Transl Sci. 2017 Sep;10(5):404-411. doi: 10.1111/cts.12479. Epub 2017 Jul 20. PubMed PMID: 28727908; PubMed Central PMCID: PMC5593169.
3: Lu J, Byrne N, Wang J, Bricogne G, Brown FK, Chobanian HR, Colletti SL, Di Salvo J, Thomas-Fowlkes B, Guo Y, Hall DL, Hadix J, Hastings NB, Hermes JD, Ho T, Howard AD, Josien H, Kornienko M, Lumb KJ, Miller MW, Patel SB, Pio B, Plummer CW, Sherborne BS, Sheth P, Souza S, Tummala S, Vonrhein C, Webb M, Allen SJ, Johnston JM, Weinglass AB, Sharma S, Soisson SM. Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40. Nat Struct Mol Biol. 2017 Jul;24(7):570-577. doi: 10.1038/nsmb.3417. Epub 2017 Jun 5. PubMed PMID: 28581512.