Bis- and mixed-tetrahydroisoquinolinium chlorofumarates: New ultra- short-acting nondepolarizing neuromuscular blockers [2]

Journal of Medicinal Chemistry

Volumn 42, Issue 2, 1999, Pages 206-209

  Boros, Eric E ^a   Bigham, Eric C ^a   Boswell, G Evan ^a   Robert A Jr , Mook ^a   Patel, Sanjay S ^a   Savarese, John J ^b   Ray, John A ^a   Thompson, James B ^a   Hashim, Mir A ^a   Wisowaty, James C ^a   Feldman, Paul L ^a   Samano, Vicente ^a  

^a GLAXOSMITHKLINE   (United States)

^b WEILL CORNELL MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

FUMARIC ACID DERIVATIVE; MIVACURIUM; NEUROMUSCULAR BLOCKING AGENT; SUXAMETHONIUM; TETRAHYDROISOQUINOLINIUM CHLOROFUMARATE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; CONTROLLED STUDY; DOSE TIME EFFECT RELATION; DRUG POTENCY; INTRAVENOUS DRUG ADMINISTRATION; LETTER; NEUROMUSCULAR BLOCKING; NONHUMAN; RHESUS MONKEY; STRUCTURE ACTIVITY RELATION;

ANIMALS; FUMARATES; MACACA MULATTA; MALE; MOLECULAR STRUCTURE; NEUROMUSCULAR NONDEPOLARIZING AGENTS;

EID: 0032930927     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm980597h     Document Type: Letter

References (25)

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4. 95 dose is defined by the FDA as ultra-short (8 min), short (20 min), intermediate (50 min), and long (≫50 min) acting; see: Bedford, R. F. From the FDA. Anesthesiology 1995, 82, 33A.
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9. (a) Patel, S. S.; Maehr, R. B.; Savarese, J. J.; Jackson, M. M.; Wastila, W. B.; Wisowaty, J. C. Neuromuscular blocking activity of cyclic and acyclic bis-quaternary ammonium analogues of mivacurium chloride in the cat. Eur. J. Pharm. Sci. 1997, 5, 253-266 and references therein.
10. (b) For the preparation of nonsymmetrical short-acting tetrahydroisoquinolinium NMBs, see: Dhar, N. C.; Maehr, R. B.; Masterson, L. A.; Midgley, J. M.; Stenlake, J. B.; Wastila, W. B. Approaches to Short-Acting Neuromuscular Blocking Agents: Nonsymmetrical Bis-tetrahydroisoquinolinium Mono-and Diesters. J. Med. Chem. 1996, 39, 556-561.
11. 95) will be reported in due course.
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14. 2 as eluent with 0.25 mL of methanesulfonic acid/ L.
15. The enantio-and regiocontrolled syntheses of 6a and 6b will be described elsewhere.
16. Feuer, H.; Rubinstein, H. Preparation of 1-(3′,1′H,6′-Pyridazinone)-3,6-pyridazinedione. Attempts to Prepare Bicyclic Dimaleic Hydrazide. J. Org. Chem. 1959, 24, 811-813.
17. Savarese, J. J. Mivacurium: A Comparison With Other Benzylisoquinolinium Nondepolarizing Muscle Relaxants. J. Drug Dev. 1993, 5, 1-5.
18. 1a
19. 95) was computed from the linear regression slopes of log-probit plots of dose versus percent block. The onset at each dose was determined from the time of injection to the time of peak inhibition of the twitch response. The duration at each dose was determined from the time of injection to the time of recovery of the twitch to 95% of baseline.
20. 1b
21. Patel, S. S.; Maehr, R. B.; Savarese, J. J.; Jackson, M. M.; Wastila, W. B.; Wisowaty, J. C. Unpublished results.
22. Bowman, W. C.; Rodger, I. W.; Houston, J.; Marshall, R. J.; McIndewar, I. Structure:action Relationships Among Some Desacetoxy Analogues of Pancuronium and Vecuronium in the Anesthetized Cat. Anesthesiology 1988, 69, 57-62.
23. Compound 6a has a half-life of 178 days in pH 3 saline at 23 °C. The half-life of 6a at 37 °C in pH 7.4 phosphate buffer is 37 min.
24. Accumulated data indicate that plasma esterases are not involved in the metabolism of 6a; this will be the focus of a future publication.
25. This rare but well-known problem has been observed in the clinical application of both mivacurium and succinylcholine; see: Frampton, J. E.; McTavish, D. Mivacurium: A Review of its Pharmacology and Therapeutic Potential in General Anaesthesia. Drugs 1993, 45, 1066-1089.