CRX-555   

GtoPdb Ligand ID: 10091

Synonyms: CRX555 | N-[(3R)-3-(Octanoyloxy)myristoyl]-O-[2-[[(3R)-3-(octanoyloxy)myristoyl]amino]-3-O-[(3R)-3-(octanoyloxy)myristoyl]-4-O-phosphono-2-deoxy-beta-D-glucopyranosyl]-L-serine
Compound class: Synthetic organic
Comment: CRX-555 is a synthetic Toll-like receptor 4 (TLR4) partial agonist from the Corixa Corporation [9]. It is one of a series of lipid A mimetic aminoalkyl glucosaminide phosphate compounds that were synthesised with different length secondary acyl chains. CRX-555 has 8 carbon atoms in each of its 3 secondary acyl chains. The chemical structures for aminoalkyl glucosaminide phosphate lipid A mimetics including CRX-555 were originally claimed in patent US6303347B1 (now expired) TLR4 as potential adjuvants and immunoeffectors [8]. A later patent (WO2008128997A1 [4]) claims these compounds for prophylactic and therapeutic applications in autoimmune diseases. The partial agonist effect of CRX-555 was demonstrated in HeLa cells transfected with TLR4/MD-2/CD14 and an IL-8 luciferase promoter construct. While CRX-527 gave a maximum stimulation of almost 60-fold (at 10μg/ml), the maximum stimulation by CRX-555 at this concentration was only ~25-fold [9].
2D Structure
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Physico-chemical Properties
Hydrogen bond acceptors 21
Hydrogen bond donors 6
Rotatable bonds 73
Topological polar surface area 315.96
Molecular weight 1402.97
XLogP 22.5
No. Lipinski's rules broken 4
SMILES / InChI / InChIKey
Canonical SMILES CCCCCCCCCCCC(CC(=O)NC1C(OCC(C(=O)O)NC(=O)CC(OC(=O)CCCCCCC)CCCCCCCCCCC)OC(C(C1OC(=O)CC(OC(=O)CCCCCCC)CCCCCCCCCCC)OP(=O)(O)O)CO)OC(=O)CCCCCCC
Isomeric SMILES CCCCCCCCCCC[C@H](CC(=O)N[C@H]1[C@H](OC[C@@H](C(=O)O)NC(=O)C[C@H](OC(=O)CCCCCCC)CCCCCCCCCCC)O[C@@H]([C@H]([C@@H]1OC(=O)C[C@H](OC(=O)CCCCCCC)CCCCCCCCCCC)OP(=O)(O)O)CO)OC(=O)CCCCCCC
InChI InChI=1S/C75H139N2O19P/c1-7-13-19-25-28-31-34-40-43-49-60(91-67(81)52-46-37-22-16-10-4)55-65(79)76-63(74(85)86)59-90-75-71(77-66(80)56-61(92-68(82)53-47-38-23-17-11-5)50-44-41-35-32-29-26-20-14-8-2)73(72(64(58-78)94-75)96-97(87,88)89)95-70(84)57-62(93-69(83)54-48-39-24-18-12-6)51-45-42-36-33-30-27-21-15-9-3/h60-64,71-73,75,78H,7-59H2,1-6H3,(H,76,79)(H,77,80)(H,85,86)(H2,87,88,89)/t60-,61-,62-,63+,64-,71-,72-,73-,75-/m1/s1
InChI Key WNFNQTGQGFHQLU-NRBIUWCVSA-N
References
1. Alderson MR, McGowan P, Baldridge JR, Probst P. (2006)
TLR4 agonists as immunomodulatory agents.
J. Endotoxin Res., 12 (5): 313-9. [PMID:17059695]
2. Cluff CW, Baldridge JR, Stöver AG, Evans JT, Johnson DA, Lacy MJ, Clawson VG, Yorgensen VM, Johnson CL, Livesay MT et al.. (2005)
Synthetic toll-like receptor 4 agonists stimulate innate resistance to infectious challenge.
Infect. Immun., 73 (5): 3044-52. [PMID:15845512]
3. Fort MM, Mozaffarian A, Stöver AG, Correia Jda S, Johnson DA, Crane RT, Ulevitch RJ, Persing DH, Bielefeldt-Ohmann H, Probst P et al.. (2005)
A synthetic TLR4 antagonist has anti-inflammatory effects in two murine models of inflammatory bowel disease.
J. Immunol., 174 (10): 6416-23. [PMID:15879143]
4. Goriely S, De WD, Goldman M, Detienne S, Brulet J-M. (2008)
Aminoalkyl glucosamine phosphate compounds for treating autoimmune diseases.
Patent number: WO2008128997A1. Assignee: Universite Libre De Bruxelles. Priority date: 19/04/2007. Publication date: 30/10/2008.
5. Gregg KA, Harberts E, Gardner FM, Pelletier MR, Cayatte C, Yu L, McCarthy MP, Marshall JD, Ernst RK. (2018)
A lipid A-based TLR4 mimetic effectively adjuvants a Yersinia pestis rF-V1 subunit vaccine in a murine challenge model.
Vaccine, 36 (28): 4023-4031. [PMID:29861179]
6. Hawkins LD, Ishizaka ST, McGuinness P, Zhang H, Gavin W, DeCosta B, Meng Z, Yang H, Mullarkey M, Young DW et al.. (2002)
A novel class of endotoxin receptor agonists with simplified structure, toll-like receptor 4-dependent immunostimulatory action, and adjuvant activity.
J. Pharmacol. Exp. Ther., 300 (2): 655-61. [PMID:11805229]
7. Huang LD, Lin HJ, Huang PH, Hsiao WC, Reddy LV, Fu SL, Lin CC. (2011)
Synthesis of serine-based glycolipids as potential TLR4 activators.
Org. Biomol. Chem., 9 (7): 2492-504. [PMID:21336404]
8. Johnson DA, Sowell CG. (2001)
Aminoalkyl glucosaminide phosphate compounds and their use as adjuvants and immunoeffectors.
Patent number: US6303347B1. Assignee: Corixa Corp.. Priority date: 08/05/1997. Publication date: 16/10/2001.
9. Stöver AG, Da Silva Correia J, Evans JT, Cluff CW, Elliott MW, Jeffery EW, Johnson DA, Lacy MJ, Baldridge JR, Probst P et al.. (2004)
Structure-activity relationship of synthetic toll-like receptor 4 agonists.
J. Biol. Chem., 279 (6): 4440-9. [PMID:14570885]
10. Zaffaroni L, Peri F. (2018)
Recent advances on Toll-like receptor 4 modulation: new therapeutic perspectives.
Future Med Chem, 10 (4): 461-476. [PMID:29380635]