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Gantacurium chloride (formerly recognized as GW280430A and as AV430A) is a new experimental neuromuscular blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in surgical anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation. Gantacurium is not yet available for widespread clinical use: it is currently undergoing Phase III clinical development. ==History== Gantacurium represents the third generation of tetrahydroisoquinolinium (THIQ) neuromuscular blocking drugs in a long lineage of compounds invented by medicinal chemists and scientists at Burroughs Wellcome Co., Research Triangle Park, North Carolina. Unlike all other clinically used tetrahydroisoquinolinium agents except cisatracurium, gantacurium is a stereo- and regioselective single isomer. And unlike any other traditional symmetrical predecessors in the family of ''bis''benzyltetrahydroisoquinolinium neuromuscular-blocking drugs, gantacurium is an ''asymmetric'' ''bis''-onium ester of α-chlorofumaric acid: this particular feature arises solely from the (1''R'')-''trans'' ''benzyl''tetrahydroisoquinolinium moiety at one onium head and a (1''S'')-''trans'' ''phenyl''tetrahydroisoquinolinium moiety at the other onium head. The chlorine atom lies on the same side of the double bond as the benzyl-THIQ moiety (or the opposite side to the phenyl-THIQ moiety). Although the carboxylic acid groups are in opposite relationship across the double bond, as in fumaric acid (dioic acid ), the chlorine atom is given the higher priority, so it's named as a (''Z'')-configuration at this stereobond. The lineage of compounds leading to the rational discovery of gantacurium stems from seminal research in tetrafluorosuccinic acid-derived ''bis''benzyltetrahydroisoquinolinium esters first synthesized in February 1991 by a postdoctoral Fellow (Sanjay S. Patel, PhD) and James C. Wisowaty, PhD, in the Chemical Development Laboratories at Burroughs Wellcome Co. in collaboration with John J. Savarese, MD (Chairman of Anesthesiology at the New York Presbyterian-Weill Cornell Medical Center, New York City). The synthesis of symmetrical halofumarate and halosuccinate esters was prompted by initial attempts to make ''bis''-onium tetrafluorosuccinic acid esters (compound 551U91〔 and 552U91〔)—the novel idea of a tetrafluorosuccinate linker between two onium heads being prompted by Roy A Swaringen, PhD (the then Group Director of Chemical Development Laboratories at Burroughs Wellcome Co.). It was very quickly realized, however, that the tetrafluorosuccinic acid esters were too unstable for isolation in sufficient quantities for extensive ''in vitro'' or ''in vivo'' preclinical evaluations. To circumvent the ''in situ'' instability of the fluoro derivatives, synthesis of ''bis''-onium dichloro- and dibromosuccinates was undertaken: that in itself lead to complex intractable mixtures of mono- and di-halofumarate and halosuccinate compounds. The mixtures were inseparable initially but proved to be promising: ''in vivo'' tests of these mixtures (798W92 and 799W92) in a cat model pointed to potential leads for a compound with the highly prized duality of a rapid onset of action and an ultrashort duration of action (see below for definition of ultrashort duration). This led to the synthesis of prototypical ''bis''benzyltetrahydroisoquinolinium halofumarate esters in April 1992: compounds 1710W92 (a monochlorofumarate) and 1975W92 (a dichlorofumarate), both of which were noted for their ultrashort durations of action, and would differ structurally only very slightly from the future gantacurium in their stereochemistry and symmetry. Indeed, the idea of exploring asymmetric tetrahydroisoquinolinium esters had already been seeded with parallel and earlier syntheses of another series of asymmetric potential neuromuscular blocking agents, although the original concept for asymmetricity in the design of new neuromuscular blocking drugs dates back to 1962 with reported combinations of the respective halves of laudexium and succinylcholine (suxamethonium) modeled, presumably, on the asymmetric structure of the prototypical neuromuscular blocking agent ''d''-tubocurarine that made its entry into anesthetic practice on 23 January 1942, at the Montreal Homeopathic Hospital. Very shortly after the breakthrough in May 1992, however, Patel relinquished his Fellowship and further progress languished until late 1993/early 1994 when the research was resumed by another team of Burroughs Wellcome Co. chemists led by Eric Bigham PhD and Evan Boswell PhD: a series of stereoselective halofumarate and halosuccinate compounds were synthesized and tested for further lead optimisation. Again, however, the untimely intervening merger between Burroughs Wellcome Co. and its rival Glaxo Inc. to form the now non-existent GlaxoWellcome Inc. during 1995 resulted in even further delays to progress in optimizing the halosuccinate and halofumarate series of neuromuscular blocking drugs. It was not until late in 1995 that further research and lead optimization was re-initiated by yet another team of medicinal chemists at GlaxoWellcome Inc. (Research Triangle Park) this time led by Eric E. Boros PhD, Robert A. Mook Jr. PhD, and Vicente Samano PhD. The team's work rapidly led to the first synthesis of GW280430A in 1996. Patents for gantacurium were subsequently applied for and issued in 1998.〔Bigham EC, Boswell GE, Savarese JJ, Swaringen RA Jr., Patel SS, Boros EE, Mook RA Jr., Samano V. Substituted isoquinolines as ultra short acting neuromuscular blockers. PCT Int. Appl. (1998), 110 pp., WO 9842675, CAN 129:275845〕〔Bigham EC, Boswell GE, Savarese JJ, Swaringen RA Jr., Patel SS, Boros EE, Mook RA Jr., Samano V. Preparation of dimeric isoquinolines as ultra short acting neuromuscular blockers. PCT Int. Appl. (1998), 49 pp., WO 9842674.〕 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Gantacurium chloride」の詳細全文を読む スポンサード リンク
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