更新于：2024-11-01

MMPs x def

更新于：2024-11-01

基本信息

关联

项与 MMPs x def 相关的药物

BB-83698

靶点

MMPs x def

作用机制

MMPs抑制剂 [+1]

在研机构-

原研机构

Ligand UK Ltd.

在研适应症-

非在研适应症

细菌感染 [+4]

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 MMPs x def 相关的临床结果

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100 项与 MMPs x def 相关的转化医学

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0 项与 MMPs x def 相关的专利（医药）

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项与 MMPs x def 相关的文献（医药）

2002-12-01·Bioorganic & Medicinal Chemistry3区 · 医学

2D-QSAR in hydroxamic acid derivatives as peptide deformylase inhibitors and antibacterial agents

3区 · 医学

Article

作者: Philip Prathipati ; Anil K Saxena ; Manish K Gupta ; Pradeep Mishra

Peptide deformylase catalyzes the removal of N-formyl group from the N-formylmethionine of ribosome synthesized polypeptide in eubacteria. Quantitative structure-activity relationship (QSAR) studies have been carried out in a series of beta-sulfonyl and beta-sulfinyl hydroxamic acid derivatives for their PDF enzyme inhibitory and antibacterial activities against Escherichia coli DC2 and Moraxella catarrhalis RA21 which demonstrate that the PDF inhibitory activity in cell free and whole cell system increases with increase in molar refractivity and hydrophobicity. The comparison of the QSARs between the cell free and whole cell system indicate that the active binding sites in PDF isolated from E. coli and in M. catarrhalis RA21 are similar and the whole cell antibacterial activity is mainly due to the inhibition of PDF. Apart from this the QSARs on some matrixmetelloproteins (COL-1, COL-3, MAT and HME) and natural endopeptidase (NEP) indicate the possibilities of introducing selectivity in these hydroxamic acid derivatives for their PDF inhibitory activity.

2002-09-01·Antimicrobial Agents and Chemotherapy2区 · 医学

N-Alkyl Urea Hydroxamic Acids as a New Class of Peptide Deformylase Inhibitors with Antibacterial Activity

2区 · 医学

Article

作者: Weidmann, Beat ; Jacobs, Jeff ; Wu, Charlotte ; Wang, Wen ; Pan, Shi-Hao ; Withers, George ; White, Richard J. ; Lewis, Jason G. ; Clark, Kirk ; Dunn, Elina ; Porter, Wilma L. ; Gu, Helen ; Yuan, Zhengyu ; Patel, Dinesh V. ; Koehn, Jim ; Mangold, James B. ; Chen, Dawn Z. ; Cramer, Jeffrey A. ; Kulathila, R. ; Lopez, S. ; Hackbarth, Corinne J. ; Margolis, Peter S. ; Trias, Joaquim

ABSTRACTPeptide deformylase (PDF) is a prokaryotic metalloenzyme that is essential for bacterial growth and is a new target for the development of antibacterial agents. All previously reported PDF inhibitors with sufficient antibacterial activity share the structural feature of a 2-substituted alkanoyl at the P1′ site. Using a combination of iterative parallel synthesis and traditional medicinal chemistry, we have identified a new class of PDF inhibitors withN-alkyl urea at the P1′ site. Compounds with MICs of ≤4 μg/ml against gram-positive and gram-negative pathogens, includingStaphylococcusaureus,Streptococcuspneumoniae, andHaemophilusinfluenzae, have been identified. The concentrations needed to inhibit 50% of enzyme activity (IC50s) forEscherichiacoliNi-PDF were ≤0.1 μM, demonstrating the specificity of the inhibitors. In addition, these compounds were very selective for PDF, with IC50s of consistently >200 μM for matrilysin and other mammalian metalloproteases. Structure-activity relationship analysis identified preferred substitutions resulting in improved potency and decreased cytotoxity. One of the compounds (VRC4307) was cocrystallized with PDF, and the enzyme-inhibitor structure was determined at a resolution of 1.7 Å. This structural information indicated that the urea compounds adopt a binding position similar to that previously determined for succinate hydroxamates. Two compounds, VRC4232 and VRC4307, displayed in vivo efficacy in a mouse protection assay, with 50% protective doses of 30.8 and 17.9 mg/kg of body weight, respectively. TheseN-alkyl urea hydroxamic acids provide a starting point for identifying new PDF inhibitors that can serve as antimicrobial agents.