Journal of Medicinal Chemistry p. 1857 - 1864 (1994)
Update date:2022-08-04
Topics:
Starrett, John E.
Tortolani, David R.
Russell, John
Hitchcock, Michael J. M.
Whiterock, Valerie
et al.
A series of phosphonate prodrugs were evaluated in an attempt to increase the oral bioavailability of the anti-HIV agent 9-<2-(phosphonomethoxy)ethyl>adenine (PMEA; 1).The majority of the bis(alkyl ester) and bis(alkyl amide) prodrugs were prepared by alcohol or amine displacement of dichlorophosphonate 2.Basic hydrolysis of the bis(esters) or bis(amides) provides the corresponding monoesters or momoamides.Synthesis of bis<(acyloxy)alkyl> phosphonates 10a-c was accomplished by alkylation of PMEA with the appropriate chloromethyl ether in the presence of N,N'-dicyclohexylmorpholinecarboxamidine.The systemic levels of PMEA following oral administration of a PMEA prodrug to rats were determined by measuring the concentration of PMEA in the urine for 48 h after administration of the prodrug.The oral bioavailability of PMEA employing this method was determined to be 7.8percent.Oral dosing with bis(alkyl) phosphonates 3a,b resulted in apparent absorption of the prodrugs (equal or >40percent), although neither of the esters were completely cleaved to liberate the parent phosphonate PMEA.The mono(alkyl esters) 7a-e and 8a,b exhibited poor oral bioavailability (equal or <5percent).Phosphonamides 5,6, and 9 were unstable under acidic conditions and provided levels of PMEA comparable to the parent compound after oral administration.Bis<(acyloxy)alkyl> phosphonates 10a-c demonstrated significantly improved oral bioavailabilities of 17.6percent, 14.6percent, and 15.4percent, respectively.When evaluated in vitro against HSV-2, (acyloxy)alkyl phosphonates 10a-c were greater than 200-fold more active than PMEA.
View MoreJinTan Pingsheng Chemical Co.,Ltd
Contact:+86-519-82828200
Address:NO.11Danfengxilu Road,Jintan City,Jiangsu,China
Contact:+86-633-8332928
Address:No.1,Huanghai Yilu.Rizhao,Shandong
Xiamen Goodhealth Pharmchem Co., Ltd.
Contact:0086-592-2097683
Address:404R No.2 54# Minzu Rd., Xiamen, China
Shanghai Bojing Chemical Co., Ltd.
Contact:021-37122233
Address:6F Buildiing 11,No.388,Baifu Road,District Fengxian.Shanghai, China.
Zhejiang Sanmei Chemical Industry Co., Ltd
Contact:86-579-87633213
Address:Huchu Industrial Zone, Qingnian Rd., Wuyi County, Zhejiang Prov., China.
Doi:10.1080/00397910802238791
(2008)Doi:10.1039/c8sc01089g
(2018)Doi:10.1016/j.jphotochem.2012.08.012
(2012)Doi:10.1016/j.molstruc.2012.11.001
(2013)Doi:10.1016/j.bmcl.2013.01.075
(2013)Doi:10.1021/om3012695
(2013)