Optically Active Cyclohexene Derivative as a New Antisepsis Agent: An Efficient Synthesis of Ethyl (6R)-6-[N-(2-Chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242)

Abstract

Sepsis and septic shock remain the chief causes of death in intensive care units, with mortality rates between 30 and 70%.1-3) Although several drug candidates have entered clinical trials over the last 20 years, most have not demonstrated significant benefit for patients with sepsis and septic shock, and difficulties of the development of an antisepsis agent has been proven. In 2001, Drotrecogin-a (Xigris TM ), 4) a recombinant human activated protein C, was launched onto the market as the first antisepsis agent, but the usefulness of this drug is limited due to its efficacy and safety.Recently, we reported that ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate [TAK-242: (R)-1] was selected as a new class of clinical candidate for sepsis.5) TAK-242 exhibited potent inhibitory activity for the production of not only nitric oxide (NO) but also various cytokines such as tumor necrosis factor-alfa (TNF-a), interleukin-1-beta (IL-1b) and IL-6 in vitro, as well as potent protective effects in the mouse endotoxin shock model. (R)-1 is currently undergoing clinical trails and is expected to be a promising antisepsis drug.As shown in Chart 1, (R)-1 was obtained in high enantiomeric purity by the optical resolution of rac-1, prepared from commercially available ethyl 2-oxocyclohexane-1-carboxylate (2) in three steps, by means of preparative high performance liquid chromatography (HPLC) using a chiral stationary phase. 5) Although separation using preparative HPLC is a straightforward method for the preparation of small quantities of optically active compounds, applications to large scale production are sometimes troublesome. Thus, an efficient and practical process for the preparation of optically active (R)-1 was required in order to supply sufficient quantities for further evaluation of this compound. In this paper, we describe the development of two new synthetic methods of (R)-1 utilizing rac-1 as the synthetic precursor.In order to find an alternative synthesis of optically active (R)-1 from the rac-1, the following two routes were proposed (Chart 2): the formation and separation of diastereomeric ester derivatives I followed by the conversion to ethyl ester (Route A), and enzymatic hydrolysis of the ester derivative (if necessary, followed by ethyl esterification, Route B).The synthetic method via the preparation of diastereomeric phenethyl ester derivatives was initially investigated as shown in Chart 3. First, the synthesis of key intermediate carboxylic acid 3 by hydrolysis of rac-1 was examined using standard hydrolytic conditions employing bases such as sodium hydroxide (NaOH), lithium hydroxide, potassium carbonate (K 2 CO 3 ) and cesium carbonate (Cs 2 CO 3 ) or Lewis acids and Brønsted acids. However, in all cases hydrolysis was accompanied by significant decomposition resulting in low yields of 3. In further studies, the use of barium dihydroxide [Ba(OH) 2 ] was found to give 3 in good yield. Thus, the treatment of rac-1 with aqueous Ba(OH) 2 solution at 60°C in acetonitrile (...

Pharmacological inhibition of TLR4-NOX4 signal protects against neuronal death in transient focal ischemia

“…1A)} was synthesized using a procedure based on a previous report38, at laboratory of Pharmaceutical and Medicinal Chemistry, Department of Organic and Medicinal Chemistry, Gifu Pharmaceutical University. The compound was identified by 1H-NMR and Mass spectra (see Supplementary Information.)…”

Inhibition of intimal hyperplasia in murine aortic allografts by administration of a small-molecule TLR4 inhibitor TAK-242

“…TAK-242 (resatorvid), a small-molecule specific inhibitor of TLR4 signaling, inhibits the production of lipopolysaccharide (LPS)-induced inflammatory mediators by binding to the intracellular domain TIRAP of TLR4 9 . As a result, it completely prevents NF-κB DNA binding, and accordingly represses expression of IL-1β, IL-6, TNF-α, MIP-2 and CCL2 10 . In phase III clinical trials, TAK-242 has demonstrated promising efficacy as an antisepsis agent 11 , 12 .…”

Transcriptomics Changes in the Peritoneum of Mice with Lipopolysaccharide-Induced Peritonitis

“…TAK 242 (resatorvid) is a specific TLR4 inhibitor that has potent anti-inflammatory activity in a variety of inflammatory diseases [ 20 , 21 , 22 , 23 , 24 , 25 ], including endotoxemia-induced skeletal muscle wasting [ 37 ], sepsis [ 20 , 22 , 24 , 38 ], acute kidney injury [ 39 ], neuroinflammation [ 40 ], acute cerebral ischemia [ 41 ], cancer [ 42 ], and rheumatoid arthritis [ 43 ].…”

“…The binding of LPS to TLR4 leads to the activation of a series of downstream signaling pathways, which play a fundamental role in various physiological processes [ 18 , 19 ]. TAK 242 (resatorvid) is a TLR4 inhibitor [ 20 , 21 , 22 , 23 , 24 , 25 ], which can suppress a series of cytological events in inflammation, including inflammatory cytokine production, inflammatory gene expression, and inflammation-related pathways activation [ 20 , 23 ]. However, to the best of our knowledge, the effect of TLR4 (Toll-like receptor 4) inhibitor on the transcriptomics of LPS-mediated mouse peritonitis has not been reported yet.…”