Effect of the acyl groups on O→N acyl migration in the water-soluble Prodrugs of HIV-1 protease inhibitor

被引：25

作者：

Hamada, Y ^{[1
]}

Matsumoto, H ^{[1
]}

Kimura, T ^{[1
]}

Hayashi, Y ^{[1
]}

Kiso, Y ^{[1
]}

机构：

[1] Kyoto Pharmaceut Univ, Dept Med Chem, Ctr Frontier Res Med Sci, Yamashima Ku, Kyoto 6078412, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2003年 / 13卷 / 16期

关键词：

D O I：

10.1016/S0960-894X(03)00576-6

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

To improve the low water-solubility of HIV-1 protease inhibitors KNI-272, -279 and -727, we previously reported the water-soluble prodrugs of these inhibitors based on O-->N intramolecular acyl migration reaction. These prodrugs were rapidly converted to the corresponding parent drugs under physiological conditions. To understand the steric and electrostatic effects of O-acyl moiety on the migration rate, we examined several types of prodrug. A remarkably slow migration was observed in the benzoyl-type prodrugs, and Hammett plot of migration rate constants of p-substituted benzoyl-type prodrugs gave a linear free energy relationship. (C) 2003 Elsevier Ltd. All rights reserved.

引用

页码：2727 / 2730

页数：4

共 26 条

[1] BARROW CM, 1961, PHYSICAL CHEM, P327
[2] PEPTIDOMIMETIC HIV PROTEASE INHIBITORS - PHOSPHATE PRODRUGS WITH IMPROVED BIOLOGICAL-ACTIVITIES
CHONG, KT
RUWART, MJ
HINSHAW, RR
WILKINSON, KF
RUSH, BD
YANCEY, MF
STROHBACH, JW
THAISRIVONGS, S
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 1993, 36 (17) : 2575 - 2577
[3] CROCKFORD HB, 1966, FDN CHEM KINETICS, P317
[4] TOWARD IMPROVED ANTI-HIV CHEMOTHERAPY - THERAPEUTIC STRATEGIES FOR INTERVENTION WITH HIV-INFECTIONS
DECLERCQ, E
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 1995, 38 (14) : 2491 - 2517
[5] FROST AA, 1961, KINETICS MECH STUDY, P1
[6] New water-soluble prodrugs of HIV protease inhibitors based on O→N intramolecular acyl migration
Hamada, Y
Ohtake, J
Sohma, Y
Kimura, T
Hayashi, Y
Kiso, Y
[J]. BIOORGANIC & MEDICINAL CHEMISTRY, 2002, 10 (12) : 4155 - 4167
[7] HAMMETT LP, 1970, PHYSICAL ORGANIC CHE, P347
[8] HIV PROTEASE - A NOVEL CHEMOTHERAPEUTIC TARGET FOR AIDS
HUFF, JR
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 1991, 34 (08) : 2305 - 2314
[9] ORALLY ACTIVE WATER-SOLUBLE N,O-ACYL TRANSFER PRODUCTS OF A BETA,GAMMA-BISHYDROXYL AMIDE CONTAINING RENIN INHIBITOR
HURLEY, TR
COLSON, CE
HICKS, G
RYAN, MJ
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 1993, 36 (10) : 1496 - 1498
[10] INVITRO ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS (HIV) ACTIVITIES OF TRANSITION-STATE MIMETIC HIV PROTEASE INHIBITORS CONTAINING ALLOPHENYLNORSTATINE
KAGEYAMA, S
MIMOTO, T
MURAKAWA, Y
NOMIZU, M
FORD, H
SHIRASAKA, T
GULNIK, S
ERICKSON, J
TAKADA, K
HAYASHI, H
BRODER, S
KISO, Y
MITSUYA, H
[J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1993, 37 (04) : 810 - 817

← 1 2 3 →