Synthesis and Properties of 2-S-[2′-(N,N-Dialkylamino)ethyl]thio-1,3,2-dioxaphosphorinane 2-Oxide and of the Corresponding Quaternary Derivatives as Potential Nontoxic Antiglaucoma Agents

Gavriel Amitai, Yacov Ashani, Yona Grunfeld, Asher Kalir, Sasson Cohen

Research output: Contribution to journalArticlepeer-review

Abstract

A new series of cyclic organophosphorus esters, 2-S-[2′ -(N,N-dialkylamino)ethyl]thio-1,3,2-dioxaphosphorinane 2-oxide and their quaternary derivatives, was synthesized and studied as potential antiglaucoma agents. These compounds inhibit acetylcholinesterase (E.C. 3.1.1.7) at a bimolecular rate constant (ki) in the range of 103-104 M-1 min-1. Values of the affinity {K) and phosphorylation (k) rate constants for this enzyme indicate that k is responsible for the relatively low values of ki as compared with similar data for the open-chain analogues, O,O-diethyl phosphorothiolates (106 M-1 min-1). The mammalian toxicity of the new compounds in terms of acute LD50 values in mice is 1-3×103 less than that of phospholine, an open-chain analogue. In an initial clinical trial, one member of the new series (alkyl = C2H5) caused a significant decrease of intraocular pressure in aphakic glaucoma, while phospholine proved to be ineffective.

Original languageEnglish
Pages (from-to)810-813
Number of pages4
JournalJournal of Medicinal Chemistry
Volume19
Issue number6
DOIs
StatePublished - 1 Jun 1976
Externally publishedYes

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