Design of Helicobacter pylori glutamate racemase inhibitors as selective antibacterial agents:: A novel pro-drug approach to increase exposure

被引:29
作者
Basarab, Gregory S. [1 ]
Hill, Pamela J. [1 ]
Rastagar, Abdullah [1 ]
Webborn, Peter J. H. [2 ]
机构
[1] AstraZeneca, R&D Boston, Canc & Infect Res Area, Waltham, MA 02451 USA
[2] AstraZeneca, R&D Charnwood, Phys Metab Sci, Loughborough LE11 5RH, Leics, England
关键词
glutamate racemase; MurI; pro-drug; pyrazolopyrimidinedione;
D O I
10.1016/j.bmcl.2008.06.092
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
High-throughput screening uncovered a pyrazolopyrimidinedione hit as a selective, low micromolar inhibitor of Helicobacter pylori glutamate racemase (MurI). Variation of the substituents around the scaffold led to low nanomolar inhibitors and improved antibacterial activity. The challenge in this program was to translate excellent enzyme inhibition into potent antibacterial activity and pharmacokinetics suitable for oral therapy. Compounds were profiled for MurI inhibition, activity against H. pylori, microsomal stability, and pharmacokinetics in mice. Iterative cycles of analog synthesis and biological testing led to compounds with substituents optimized for both low MICs (<= 2 mu g/ml) and good microsomal stability. In order to achieve high bioavailability, a novel pro-drug approach was implemented wherein a solubilizing sulfoxide moiety is oxidized in vivo to a sulfone. (C) 2008 Elsevier Ltd. All rights reserved.
引用
收藏
页码:4716 / 4722
页数:7
相关论文
共 32 条
[1]  
BASARAB G, Patent No. 7285558
[2]  
Blaser MJ, 2004, J CLIN INVEST, V113, P321, DOI [10.1172/JCI200420925, 10.1172/JCI20925]
[3]   A CONVENIENT METHOD FOR THE PREPARATION OF (ALKYLSULFONYL)BENZOIC ACIDS [J].
BROWN, RW .
JOURNAL OF ORGANIC CHEMISTRY, 1991, 56 (16) :4974-4976
[4]  
CHESHIRE D, Patent No. 6028074
[5]   Synthesis of sulfone-substituted furan chromophores with high molecular hyperpolarizability [J].
Chou, SSP ;
Shen, CH .
TETRAHEDRON LETTERS, 1997, 38 (36) :6407-6410
[6]   4-Substituted D-glutamic acid analogues:: The first potent inhibitors of glutamate racemase (MurI) enzyme with antibacterial activity [J].
de Dios, A ;
Prieto, L ;
Martín, JA ;
Rubio, A ;
Ezquerra, J ;
Tebbe, M ;
de Uralde, BL ;
Martín, J ;
Sánchez, A ;
LeTourneau, DL ;
McGee, JE ;
Boylan, C ;
Parr, TR ;
Smith, MC .
JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (20) :4559-4570
[7]   Structure and function of the Mur enzymes: development of novel inhibitors [J].
El Zoeiby, A ;
Sanschagrin, F ;
Levesque, RC .
MOLECULAR MICROBIOLOGY, 2003, 47 (01) :1-12
[8]   MECHANISM OF THE REACTION CATALYZED BY GLUTAMATE RACEMASE [J].
GALLO, KA ;
TANNER, ME ;
KNOWLES, JR .
BIOCHEMISTRY, 1993, 32 (15) :3991-3997
[9]   Active site residues of glutamate racemase [J].
Glavas, S ;
Tanner, ME .
BIOCHEMISTRY, 2001, 40 (21) :6199-6204
[10]  
HE RHY, 1998, J CHEM RES SYNOP, V12, P786