WAY-204688

WAY-204688, also known as SIM-688, is a synthetic nonsteroidal estrogen and nuclear factor κB (NF-κB) inhibitor which was originated by ArQule and Wyeth and was under development by Wyeth for the treatment of rheumatoid arthritis, non-specific inflammation, and sepsis but was never marketed.[1][2][3] It is a "pathway-selective" estrogen receptor (ER) ligand which inhibits NF-κB with an IC50Tooltip half-maximal inhibitory concentration of 122 nM and with maximal inhibition relative to estradiol of 94%.[3][4] Inhibition of NF-κB by WAY-204688 appears to be dependent on agonism of the ERα, as it is reversed by the ERα antagonist fulvestrant, but is not dependent on the ERβ.[3][4] In contrast to the case of NF-κB inhibition, WAY-204688 produces only slight elevation of creatine kinase in vitro, a measure of classical estradiol effects.[3][4] It reached phase I clinical trials prior to the discontinuation of its development.[1]

WAY-204688
Clinical data
Drug classNonsteroidal estrogen; Nuclear factor κB inhibitor
Identifiers
  • (2S)-2-[(S)-(2-methoxyphenyl)naphthalen-1-ylmethyl]-2-methyl-3-oxo-3-[4-[3-(trifluoromethyl)phenyl]piperidin-1-yl]propanenitrile
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC34H31F3N2O2
Molar mass556.629 g·mol−1
3D model (JSmol)
  • C[C@@](C#N)([C@H](C1=CC=CC=C1OC)C2=CC=CC3=CC=CC=C32)C(=O)N4CCC(CC4)C5=CC(=CC=C5)C(F)(F)F
  • InChI=1S/C34H31F3N2O2/c1-33(22-38,32(40)39-19-17-23(18-20-39)25-11-7-12-26(21-25)34(35,36)37)31(29-14-5-6-16-30(29)41-2)28-15-8-10-24-9-3-4-13-27(24)28/h3-16,21,23,31H,17-20H2,1-2H3/t31-,33+/m0/s1
  • Key:JZPONCMNBSEYQW-CQTOTRCISA-N

References
  1. "SIM 688 - AdisInsight".
  2. Ivanenkov YA, Balakin KV, Lavrovsky Y (January 2011). "Small molecule inhibitors of NF-kB and JAK/STAT signal transduction pathways as promising anti-inflammatory therapeutics". Mini Reviews in Medicinal Chemistry. 11 (1): 55–78. doi:10.2174/138955711793564079. PMID 21034406.
  3. Dodge JA, Richardson TI (2007). "Chapter 10 Novel Selective Estrogen Receptor Modulators (SERMs)". Annual Reports in Medicinal Chemistry Volume 42. Annual Reports in Medicinal Chemistry. Vol. 42. pp. 147–160. doi:10.1016/S0065-7743(07)42010-3. ISBN 9780123739124. ISSN 0065-7743.
  4. Opal SM, Palardy JE, Cristofaro P, Parejo N, Jhung JW, Keith JC, et al. (December 2005). "The activity of pathway-selective estrogen receptor ligands in experimental septic shock". Shock. 24 (6): 535–540. doi:10.1097/01.shk.0000183388.90895.cb. PMID 16317384. S2CID 12169698.
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