Synthesis and evaluation of novel amidate prodrugs of PMEA and PMPA

被引：64

作者：

Ballatore, C

McGuigan, C

De Clercq, E

Balzarini, J

机构：

[1] Univ Wales Coll Cardiff, Welsh Sch Pharm, Cardiff CF10 3XF, S Glam, Wales

[2] Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2001年 / 11卷 / 08期

关键词：

D O I：

10.1016/S0960-894X(01)00128-7

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Some novel amidate prodrugs of PMEA and PMPA have been synthesised and tested in vitro for their biological activity. Compound 5 in particular showed greatly enhanced antiviral potency compared with the parent nucleotide analogue. In vitro enzymatic studies and structure-activity relationships indicate that the degradation mechanism of such prodrugs may be the same as that described for the phosphoramidate triesters of nucleotide analogues. (C) 2001 Elsevier Science Ltd. All rights reserved.

引用

收藏

页码：1053 / 1056

页数：4

相关论文

共 18 条

[1] Synthesis, in vitro biological evaluation and oral bioavailability of 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) prodrugs [J].

Arimilli, MN ;

Kim, CU ;

Dougherty, J ;

Mulato, A ;

Oliyai, R ;

Shaw, JP ;

Cundy, KC ;

Bischofberger, N .

ANTIVIRAL CHEMISTRY & CHEMOTHERAPY, 1997, 8 (06) :557-564

[2] Marked inhibitory activity of masked aryloxy aminoacyl phosphoramidate derivatives of dideoxynucleoside analogues against visna virus infection [J].

Balzarini, J ;

Cahard, D ;

Wedgwood, O ;

Salgado, A ;

Velázquez, T ;

Yarnold, CJ ;

De Clercq, E ;

McGuigan, C ;

Thormar, H .

JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY, 1998, 17 (04) :296-302

[3] Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives [J].

Balzarini, J ;

Karlsson, A ;

Aquaro, S ;

Perno, CF ;

Cahard, D ;

Naesens, L ;

DeClercq, E ;

McGuigan, C .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (14) :7295-7299

[4] Activity of the (R)-enantiomers of 9-(2-phosphonylmethoxypropyl)-adenine and 9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine against human immunodeficiency virus in different human cell systems [J].

Balzarini, J ;

Aquaro, S ;

Perno, CF ;

Witvrouw, M ;

Holy, A ;

DeClercq, E .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1996, 219 (02) :337-341

[5]

DECLERCQ E, 1987, ANTIVIR RES, V8, P261

[6] Cidofovir, a new agent with potent anti-herpesvirus activity [J].

Hitchcock, MJM ;

Jaffe, HS ;

Martin, JC ;

Stagg, RJ .

ANTIVIRAL CHEMISTRY & CHEMOTHERAPY, 1996, 7 (03) :115-127

[7]

LEE WA, 2000, 14 INT ROUNDT NUCL N

[8] THE CHEMISTRY OF PHOSPHAPEPTIDES - INVESTIGATIONS ON THE SYNTHESIS OF PHOSPHONAMIDATE, PHOSPHONATE, AND PHOSPHINATE ANALOGS OF GLUTAMYL-GAMMA-GLUTAMATE [J].

MALACHOWSKI, WP ;

COWARD, JK .

JOURNAL OF ORGANIC CHEMISTRY, 1994, 59 (25) :7625-7634

[9] Synthesis, anti-human immunodeficiency virus activity and esterase lability of some novel carboxylic ester-modified phosphoramidate derivatives of stavudine (d4T) [J].

McGuigan, C ;

Sutton, PW ;

Cahard, D ;

Turner, K ;

O'Leary, G ;

Wang, Y ;

Gumbleton, M ;

De Clercq, E ;

Balzarini, J .

ANTIVIRAL CHEMISTRY & CHEMOTHERAPY, 1998, 9 (06) :473-479

[10] Novel nucleoside phosphoramidates as inhibitors of HIV: Studies on the stereochemical requirements of the phosphoramidate amino acid [J].

McGuigan, C ;

Salgado, A ;

Yarnold, C ;

Harries, TY ;

DeClercq, E ;

Balzarini, J .

ANTIVIRAL CHEMISTRY & CHEMOTHERAPY, 1996, 7 (04) :184-188