243984-11-4Relevant articles and documents
Ex-vivo generation of drug-eluting islets improves transplant outcomes by inhibiting TLR4-Mediated NFkB upregulation
Chang, Charles A.,Akinbobuyi, Babatope,Quintana, Jeremy M.,Yoshimatsu, Gumpei,Naziruddin, Bashoo,Kane, Robert R.
, p. 13 - 24 (2018/01/10)
The systemic administration of immunosuppressive and anti-inflammatory drugs is routinely employed in organ transplantation to minimize graft rejection and improve graft survival. Localized drug delivery has the potential to improve transplant outcomes by providing sustained exposure to efficacious drug concentrations while avoiding systemic immunosuppression and off-target effects. Here, we describe the synthesis of a novel prodrug and its direct covalent conjugation to pancreatic islets via a cleavable linker. Post-transplant, linker hydrolysis results in the release of a potent anti-inflammatory antagonist of TLR4, localized to the site of implantation. This covalent islet modification significantly reduces the time and the minimal effective dose of islets necessary to achieve normoglycemia in a murine transplantation model. In streptozotocin-induced diabetic C57BL/6 mice a syngeneic transplant of ～100 modified islets achieved a 100% cure rate by the end of a 4-week monitoring period, compared to a 0% cure rate for untreated control islets. Overall, this direct prodrug conjugation to islets is well tolerated and preserves their functionality while affording significantly superior transplant outcomes. The development of drug-eluting tissues that deliver sustained and localized doses of small-molecule therapeutics represents a novel pathway for enhancing success in transplantation.
SUBSTITUTED CYCLOHEXENES
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Page/Page column 66, (2009/03/07)
Disclosed herein are deuterated derivatives of TAK-242 of Formula (I) which are modulators of TLR4 signalling pathway, pharmaceutical compositions thereof and methods of use thereof. Formula (I)
Convenient synthesis of antisepsis agent TAK-242 by novel optical resolution through diastereomeric N-acylated sulfonamide derivative
Nishiguchi, Atsuko,Ikemoto, Tomomi,Tomimatsu, Kiminori
, p. 4048 - 4051 (2007/10/03)
A convenient synthesis method of antisepsis agent TAK-242 ((R)-1) through diastereomeric resolution was developed. By condensation of racemate rac-1 with chiral acid (S)-O-acetylmanderic acid (6a), the desired diastereomer 5a was isolated with 98% de in 39% yield by simple crystallization. Deacylation of 5a with aq NaOH followed by recrystallization provided (R)-1 with 99% ee in 20% yield from rac-1.
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)
Yamada,Ichikawa,Yamano,Kikumoto,Nishikimi,Tamura,Kitazaki
, p. 58 - 62 (2007/10/03)
Two new synthetic methods were established for the efficient synthesis of optically active cyclohexene antisepsis agent, ethyl (6R)-6-[N-(2-chloro-4- fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate [(R)-1: TAK-242)]. The first method involved recrystallization from methanol of the diastereomeric mixture (6RS,1′R)-7, obtained by esterification of carboxylic acid 3 with (S)-1-(4-nitrophenyl)ethanol [(S)-5)] to give the desired isomer (6R,1′R)-7 with 99% de in 32% yield. Subsequent catalytic hydrogenolysis and esterification gave (R)-1 with >99% ee. The second method employed enantioselective hydrolysis of acetoxymethyl ester 9a (prepared by alkylation of 3 with bromomethyl acetate) with Lipase PS-D to give the eutomeric enantiomer (R)-9a with excellent enantioselectivity (>99% ee) and high yield (48%). The desired (R)-1 was then obtained by transesterification with ethanol in the presence of concentrated sulfuric acid without loss of ee. Of these, the procedure employing enzymatic kinetic resolution using Lipase PS-D is the more efficient and practical preparation of (R)-1.
Discovery of novel and potent small-molecule inhibitors of NO and cytokine production as antisepsis agents: Synthesis and biological activity of alkyl 6-(N-substituted sulfamoyl)cyclohex-1-ene-1-carboxylate
Yamada, Masami,Ichikawa, Takashi,Ii, Masayuki,Sunamoto, Mie,Itoh, Katsumi,Tamura, Norikazu,Kitazaki, Tomoyuki
, p. 7457 - 7467 (2007/10/03)
To develop a new therapeutic agent for sepsis, screening of the Takeda chemical library was carried out using mouse macrophages stimulated with lipopolysaccharide (LPS) to identify a new class of small-molecule inhibitors of inflammatory mediator production. The lead compound 5a was discovered, from which a series of novel cyclohexene derivatives I bearing a sulfamoyl and ester group were designed, synthesized and tested for their inhibitory activity against nitric oxide (NO) production. Derivatives I were synthesized by the coupling of sulfonyl chlorides and anilines with concomitant double bond migration in the presence of triethylamine, and phenyl ring substitution and modification of the ester and cyclohexene moieties were carried out. Among the compounds synthesized, ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]- cyclohex-1-ene-1-carboxylate [(R)-(+)-5n, TAK-242] was found to exhibit the most potent suppressive activity for the production of not only NO but also inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) induced by LPS-stimulated mouse macrophages with IC 50 values of 1.8, 1.9 and 1.3 nM, respectively. It shows marked beneficial effects in vivo also. Intravenous administration of (R)-(+)-5n at doses of 0.1 mg/kg or more suppressed the production of NO and various cytokines [TNF-α, IL-6 and IL-1β] in the mouse endotoxin shock model. Furthermore, it protected mice from death dose-dependently and all mice survived at a dose of 3 mg/kg. The minimum effective dose to protect mice from lethality in this model was 0.3 mg/kg, which was consistent with those for inhibitory effects on the production of NO and cytokines. Compound CR)-(+)-5n is currently undergoing clinical trials for the treatment of sepsis.
PROCESS FOR PREPARATION OF OPTICALLY ACTIVE SULFONAMIDES AND INTERMEDIATES FOR THEIR SYNTHESIS
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, (2008/06/13)
A method including resolution of a diastereomeric mixture represented by the formula wherein R1 and R2 are the same or different and each is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, only one of R1 and R2 contains one asymmetric carbon, and Ra is an optically active and optionally substituted hydrocarbon group or an optically active and optionally substituted heterocyclic group, or a salt thereof, to produce the diastereomer having a steric configuration of the asymmetric carbon for R1 or R2 of an R configuration or an S configuration, or a salt thereof.
