Amitai G, Ashani Y, Grunfeld Y, Kalir A, Cohen S
J Med Chem. 1976 Jun;19(6):810-3. doi: 10.1021/jm00228a600.
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. Thes compounds inhibit acetylcholinesterase (E.C.3.1.1.7)at a bimoecular rate constant (ki) in the range of 10(3)-10(4) 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 (10(6) M-1 min-1). The mammalian toxicity of the new compounds in terms of acute LD50 values in mice is 1-3 x 10(3) 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.
合成了一系列新的环状有机磷酸酯，即2-S-[2'-N,N-二烷基氨基)乙基]硫代-1,3,2-二氧磷杂环己烷2-氧化物及其季铵衍生物，并作为潜在的抗青光眼药物进行了研究。这些化合物以10(3)-10(4) M-1 min-1范围内的双分子速率常数（ki）抑制乙酰胆碱酯酶（E.C.3.1.1.7）。该酶的亲和力（K）和磷酸化（k'）速率常数的值表明，与开链类似物O,O-二乙基硫代磷酸酯（10(6) M-1 min-1）的类似数据相比，k'导致了ki相对较低的值。就小鼠急性LD50值而言，新化合物的哺乳动物毒性比开链类似物磷酰胆碱低1-3×10(3)倍。在初步临床试验中，新系列中的一个成员（烷基 = C2H5）使无晶状体青光眼患者的眼压显著降低，而磷酰胆碱则无效。
