TAK-242

• CAT Number: I002819
• CAS Number: 243984-11-4
• Molecular Formula: C15H17NO4ClFS
• Molecular Weight: 361.8
• Purity: ≥95%
• Target: TLR
• Solubility: DMSO 10 mg/ml; DMF 10 mg/ml
• Storage: Store at -20°C
• IC50: 1.1-11 nM
• InChI: 1S/C15H17ClFNO4S/c1-2-22-15(19)11-5-3-4-6-14(11)23(20,21)18-13-8-7-10(17)9-12(13)16/h5,7-9,14,18H,2-4,6H2,1H3/t14-/m1/s1
• InChIKey: LEEIJTHMHDMWLJ-CQSZACIVSA-N
• SMILES: FC1=CC(Cl)=C(NS([C@@H]2CCCC=C2C(OCC)=O)(=O)=O)C=C1

TAK-242(CAT: I002819), also known as resatorvid, is a small-molecule inhibitor of Toll-like receptor 4 (TLR4) signaling, which plays a crucial role in the innate immune response. By selectively binding to TLR4 and disrupting its interaction with downstream signaling molecules, TAK-242 can inhibit the production of pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-1β, that contribute to the pathogenesis of various inflammatory diseases. TAK-242 has been investigated as a potential therapeutic agent for sepsis, arthritis, atherosclerosis, and other inflammatory disorders, and has shown promising results in preclinical and clinical studies.

Overview of Clinical Research

Originator: Takeda
Class: Anti-inflammatories; Small molecules; Sulfonamides
Mechanism of Action: Toll-like receptor 4 antagonists
Orphan Drug Status: No
New Molecular Entity: Yes

Reference

1. Biosci Rep. 2012 Nov 30;33(1):37-47. doi: 10.1042/BSR20120098.

TAK-242, a small-molecule inhibitor of Toll-like receptor 4 signalling, unveils
similarities and differences in lipopolysaccharide- and lipid-induced
inflammation and insulin resistance in muscle cells.

Hussey SE(1), Liang H, Costford SR, Klip A, DeFronzo RA, Sanchez-Avila A, Ely B,
Musi N.

Author information:
(1)Diabetes Division, Department of Medicine, University of Texas Health Science
Center at San Antonio, San Antonio, TX 78229, USA.

Emerging evidence suggests that TLR (Toll-like receptor) 4 and downstream
pathways [MAPKs (mitogen-activated protein kinases) and NF-κB (nuclear factor
κB)] play an important role in the pathogenesis of insulin resistance. LPS
(lipopolysaccharide) and saturated NEFA (non-esterified fatty acids) activate
TLR4, and plasma concentrations of these TLR4 ligands are elevated in obesity and
Type 2 diabetes. Our goals were to define the role of TLR4 on the insulin
resistance caused by LPS and saturated NEFA, and to dissect the independent
contribution of LPS and NEFA to the activation of TLR4-driven pathways by
employing TAK-242, a specific inhibitor of TLR4. LPS caused robust activation of
the MAPK and NF-κB pathways in L6 myotubes, along with impaired insulin
signalling and glucose transport. TAK-242 completely prevented the inflammatory
response (MAPK and NF-κB activation) caused by LPS, and, in turn, improved
LPS-induced insulin resistance. Similar to LPS, stearate strongly activated
MAPKs, although stimulation of the NF-κB axis was modest. As seen with LPS, the
inflammatory response caused by stearate was accompanied by impaired insulin
action. TAK-242 also blunted stearate-induced inflammation; yet, the protective
effect conferred by TAK-242 was partial and observed only on MAPKs. Consequently,
the insulin resistance caused by stearate was only partially improved by TAK-242.
In summary, TAK-242 provides complete and partial protection against LPS- and
NEFA-induced inflammation and insulin resistance, respectively. Thus, LPS-induced
insulin resistance depends entirely on TLR4, whereas NEFA works through
TLR4-dependent and -independent mechanisms to impair insulin action.

2. Anesthesiology. 2011 May;114(5):1130-7. doi: 10.1097/ALN.0b013e31820b8b44.

Toll-like receptor 4 inhibitor TAK-242 attenuates acute kidney injury in
endotoxemic sheep.

Fenhammar J(1), Rundgren M, Forestier J, Kalman S, Eriksson S, Frithiof R.

Author information:
(1)Department of Anaesthesia and Intensive Care, Karolinska University Hospital,
Stockholm, Sweden.

BACKGROUND: This study was conducted to investigate the role of toll-like
receptor 4 (TLR4) in mediating acute kidney injury in endotoxemic sheep using the
selective TLR4 inhibitor TAK-242.
METHODS: A randomized, controlled, experimental study was performed with 20 adult
Texel crossbred sheep. Before an Escherichia coli lipopolysaccharide infusion (3
μg · kg(-1) · h(-1) for 24 h), sheep were randomized to receive a bolus dose (2
mg/kg), followed by a continuous infusion (4 mg · kg(-1) · 24 h(-1)) of either
TAK-242 (n = 7) or vehicle (n = 7). A third group of lipopolysaccharide-treated
sheep (n = 6) received norepinephrine, titrated to maintain baseline arterial
blood pressure.
RESULTS: Endotoxin infusion established a state of hyperdynamic circulation, with
an increased cardiac index, hypotension, and tachycardia. Urine output and
creatinine clearance decreased throughout the experiment, together with
increasing plasma creatinine, blood urea nitrogen, and arterial lactate
concentrations. After 24 h, TLR4 inhibition had significantly (P ≤ 0.001)
attenuated the mean ± SEM decrease in arterial pressure (97 ± 3 vs. 71 ± 4 mmHg),
urine output (1.16 ± 0.15 vs. 0.13 ± 0.05 ml · kg(-1) · h(-1)), and creatinine
clearance (126 ± 13 vs. 20 ± 7 ml/min) compared with vehicle-treated animals.
Furthermore, arterial lactate, plasma creatinine, and blood urea nitrogen
concentrations were significantly lower in the TAK-242 group versus the
vehicle-treated animals. Compared with TLR4 inhibition, norepinephrine caused
similar effects on arterial pressure, cardiac index, and heart rate; however, it
did not attenuate the decrease in urine output or creatinine clearance.
CONCLUSIONS: These results indicate a critical role for TLR4 in impairing renal
function during ovine endotoxemia that is independent of changes in central
hemodynamics.