Amine substituted N-(1H-benzimidazol-2ylmethyl)-5,6,7,8-tetrahydro-8-quinolinamines as CXCR4 antagonists with potent activity against HIV-1

Gudmundsson, Kristjan S.; Sebahar, Paul R.; Richardson, Leah D’Aurora; Miller, John F.; Turner, Elizabeth M.; Catalano, John G.; Spaltenstein, Andrew; Lawrence, Wendell; Thomson, Michael M.; Jenkinson, Stephen

doi:10.1016/j.bmcl.2009.07.037

Cited by 50 publications

(32 citation statements)

References 17 publications

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“…1) fully preserves the biological properties of AMD3100 [20]. Considerable improvement in terms of potency and pharmacokinetic properties was achieved with the optimization of series of tetrahydroquinolinamines [21][22][23]. AMD070 (Fig.…”

Section: Introductionmentioning

confidence: 98%

Ligand-guided optimization of CXCR4 homology models for virtual screening using a multiple chemotype approach

Neves

Simões

Melo

2010

J Comput Aided Mol Des

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CXCR4 is a G-protein coupled receptor for CXCL12 that plays an important role in human immunodeficiency virus infection, cancer growth and metastasization, immune cell trafficking and WHIM syndrome. In the absence of an X-ray crystal structure, theoretical modeling of the CXCR4 receptor remains an important tool for structure-function analysis and to guide the discovery of new antagonists with potential clinical use. In this study, the combination of experimental data and molecular modeling approaches allowed the development of optimized ligand-receptor models useful for elucidation of the molecular determinants of small molecule binding and functional antagonism. The ligand-guided homology modeling approach used in this study explicitly re-shaped the CXCR4 binding pocket in order to improve discrimination between known CXCR4 antagonists and random decoys. Refinement based on multiple test-sets with small compounds from single chemotypes provided the best early enrichment performance. These results provide an important tool for structure-based drug design and virtual ligand screening of new CXCR4 antagonists.

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Section: Introductionmentioning

confidence: 98%

Ligand-guided optimization of CXCR4 homology models for virtual screening using a multiple chemotype approach

Neves

Simões

Melo

2010

J Comput Aided Mol Des

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“…anticancer, antifungal, antiviral, anti-inflammatory, etc. [5][6][7][8][9][10][11][12][13]. Among them, many drug molecules have a basic skeleton of aminomethyl benzimidazole (AMB) (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…Among them, many drug molecules have a basic skeleton of aminomethyl benzimidazole (AMB) (Figure 1). [8][9][10][11][12][13] Due to good physical properties, biocompatibility and biodegradability, polylactic acid (PLA) as an environment friendly polymer produced from renewable resource [14][15][16][17] can be used in general polymer field as packaging materials, plastic profiles, thin films, nonwovens, and clothing fibers. [18][19][20][21][22][23] Of course, for the cost reason, PLA materials are more widely used in the biomedical field as bone material, surgical sutures, eye filler, gauze dressings, drug delivery, artificial urethra, and artificial esophagus.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and characterization of a novel drug-loaded polymer, poly(lactic acid-co-aminomethyl benzimidazole)

Hao

et al. 2015

Designed Monomers and Polymers

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2015): Synthesis and characterization of a novel drug-loaded polymer, poly(lactic acid-co-aminomethyl benzimidazole), Designed Monomers and Polymers, Using aminomethyl benzimidazole (AMB) as a model of benzimidazole-type drugs, a potential biodegradable drug-loaded polymer poly(lactic acid-co-aminomethyl benzimidazole) (PLAAMB) is synthesized as designed via direct melt polycondensation starting from D,L-lactic acid (LA). When the molar feed ratio LA/AMB is 40/1, the optimal synthetic conditions, including catalyst type and dosage, polycondensation temperature, and copolymerization time are discussed. After the prepolymerization at 140°C for 8 h, using 0.4 wt% stannous oxide (SnO) as the catalyst, the melt copolymerization at 160°C for 6 h gives the copolymer with the biggest weight-average molecular weight (M w ) 5300 Da. The structure and properties of the copolymer are systematically characterized with Fourier transform infrared, 1 H NMR, gel permeation chromatography, differential scanning calorimetry, and X-ray diffraction. And the investigations on the influences of different molar feed ratios on the properties of PLAAMB show that, the copolymer PLAAMB with the biggest M w of 9400 Da can be obtained. After the drug model AMB as a monomer is introduced into polylactic acid during the condensation, the T g of the obtained PLAAMB is lower than the T g of homopolymer poly(D,L-lactic acid) (PDLLA). The M w and crystallinity of PLAAMBs can meet the requirement of drug-loaded polymers in the drug delivery.

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“…There has also been successful development of in vitro CXCR4 inhibitors in the benzimidazole [170] and imidazopiperazine [171] analogs of the AMO bicyclams, but these compounds are heavily protein bound and suffer from severe protein shift in antiviral assays [170). These bicyclam These compounds function by inhibiting serotonin receptors.…”

Section: Gpcrs Are Common Targets For Pharmaceuticalsmentioning

confidence: 99%

“…There has been limited success in the development of bicyclam derivatives such as AMD-070 ( Figure 13), which recently completed Phase I clinical trials as anti-HIV-1 chemotherapy [169] . There has also been successful development of in vitro CXCR4 inhibitors in the benzimidazole ( Figure 13) [170] and imidazopiperazine [171] analogs of the AMD bicyclams as anti-HIV-1 agents, but these compounds are heavily protein bound and suffer from severe protein shift in antiviral assays [170] suggesting that the drug concentration available in the systemic circulation would be greatly reduced by circulating albumin proteins.…”

Section: Introductionmentioning

confidence: 99%

Structure-based design of inhibitors of CXCR4.

Meier¹

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Amine substituted N-(1H-benzimidazol-2ylmethyl)-5,6,7,8-tetrahydro-8-quinolinamines as CXCR4 antagonists with potent activity against HIV-1

Cited by 50 publications

References 17 publications

Ligand-guided optimization of CXCR4 homology models for virtual screening using a multiple chemotype approach

Ligand-guided optimization of CXCR4 homology models for virtual screening using a multiple chemotype approach

Synthesis and characterization of a novel drug-loaded polymer, poly(lactic acid-co-aminomethyl benzimidazole)

Structure-based design of inhibitors of CXCR4.

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