A prodrug approach toward the development of water soluble fluoroquinolones and structure-activity relationships of quinoline-3-carboxylic acids

被引：40

作者：

Baker, WR ^{[1
]}

Cai, SP ^{[1
]}

Dimitroff, M ^{[1
]}

Fang, LM ^{[1
]}

Huh, KK ^{[1
]}

Ryckman, DR ^{[1
]}

Shang, X ^{[1
]}

Shawar, RM ^{[1
]}

Therrien, JH ^{[1
]}

机构：

[1] Chiron Corp, Seattle, WA 98119 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2004年 / 47卷 / 19期

关键词：

D O I：

10.1021/jm0497895

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A fluoroquinolone prodrug, PA2808, was prepared and shown to convert to the highly active parent drug PA2789. In vitro and in vivo activation of PA2808 by alkaline phosphatase was demonstrated using disk diffusion and rat lung infection models. The water solubility of PA2808 showed a marked increase compared to PA2789 over a pH range suitable for aerosol drug delivery. A total of 48 analogues based on PA2789 were prepared and screened against a panel of Gram-positive and Gram-negative pathogens. Incorporating a cyclopropane-fused pyrrolidine (amine g) at C-7 resulted in some of the most active analogues.

引用

收藏

页码：4693 / 4709

页数：17

相关论文

共 29 条

[1] The fluoroquinolone antibacterials: past, present and future perspectives [J].

Appelbaum, PC ;

Hunter, PA .

INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, 2000, 16 (01) :5-15

[2]

Ball P, 1998, Expert Opin Investig Drugs, V7, P761, DOI 10.1517/13543784.7.5.761

[3] Comparative tolerability of the newer fluoroquinolone antibacterials [J].

Ball, P ;

Mandell, L ;

Niki, Y ;

Tillotson, G .

DRUG SAFETY, 1999, 21 (05) :407-421

[4] Synthesis, reactivity and biochemical evaluation of 1,3-substituted azetidin-2-ones as enzyme inhibitors [J].

Beauve, C ;

Bouchet, M ;

Touillaux, R ;

Fastrez, J ;

Marchand-Brynaert, J .

TETRAHEDRON, 1999, 55 (46) :13301-13320

[5]

Blondeau JM, 1999, CLIN THER, V21, P3

[6]

Bosso J. A., 1998, Journal of Infectious Disease Pharmacotherapy, V3, P1, DOI 10.1300/J100v03n03_01

[7] FLUORONAPHTHYRIDINES AS ANTIBACTERIAL AGENTS .4. SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF 5-SUBSTITUTED-6-FLUORO-7-(CYCLOALKYLAMINO)-1,4-DIHYDRO-4-OXO-1,8-NAPHTHYRIDINE-3-CARBOXYLIC ACIDS [J].

BOUZARD, D ;

DICESARE, P ;

ESSIZ, M ;

JACQUET, JP ;

LEDOUSSAL, B ;

REMUZON, P ;

KESSLER, RE ;

FUNGTOMC, J .

JOURNAL OF MEDICINAL CHEMISTRY, 1992, 35 (03) :518-525

[8] Lung alkaline phosphatase as a marker of fibrosis in chronic interstitial disorders [J].

Capelli, A ;

Lusuardi, M ;

Cerutti, CG ;

Donner, CF .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 1997, 155 (01) :249-253

[9] Identification of human pulmonary alkaline phosphatase isoenzymes [J].

Capelli, A ;

Cerutti, CG ;

Lusuardi, M ;

Donner, CF .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 1997, 155 (04) :1448-1452

[10]

Chu D. T. W., 1991, Adv. Drug Res., V21, P39