Synthesis and SAR of novel CXCR4 antagonists that are potent inhibitors of T tropic (X4) HIV-1 replication

Skerlj, Renato T.; Bridger, Gary; McEachern, Ernest J.; Harwig, Curtis; Smith, Chris; Wilson, T.; Veale, D. R.; Yee, Helen S.; Crawford, Jason; Skupinska, Krystyna A.; Wauthy, Rossana; Yang, Wen; Zhu, Yingdan; Bogucki, David; Fluri, Maria Di; Langille, Jonathon; Huskens, Dana; Clercq, Erik De; Schols, Dominique

doi:10.1016/j.bmcl.2010.11.023

Cited by 32 publications

(26 citation statements)

References 18 publications

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“…CXCR4 antagonists in which a substituted benzylic aminomethyl group or a heterocyclic aminomethyl moiety replacing the butyl amine residue showed potent antiviral activity 88. Although these molecules contain a chiral center, the SAR studies were carried out on the racemic mixtures.…”

Section: Amd070 Derivatives: Tetrahydroquinolines-based Cxcr4 Antagonmentioning

confidence: 99%

Small Molecule Inhibitors of CXCR4

Debnath¹,

Xu²,

Grande³

et al. 2013

Theranostics

243

199

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CXCR4 is a G-protein-coupled receptor involved in a number of physiological processes in the hematopoietic and immune systems. The SDF-1/CXCR4 axis is significantly associated with several diseases, such as HIV, cancer, WHIM syndrome, rheumatoid arthritis, pulmonary fibrosis and lupus. For example, CXCR4 is one of the major co-receptors for HIV entry into target cells, while in cancer it plays an important role in tumor cell metastasis. Several promising CXCR4 antagonists have been developed to block SDF-1/CXCR4 interactions that are currently under different stages of development. The first in class CXCR4 antagonist, plerixafor, was approved by the FDA in 2008 for the mobilization of hematopoietic stem cells and several other drugs are currently in clinical trials for cancer, HIV, and WHIM syndrome. While the long-term safety data for the first generation CXCR4 antagonists are not yet available, several new compounds are under preclinical development in an attempt to provide safer and more efficient treatment options for HIV and cancer patients.

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Section: Amd070 Derivatives: Tetrahydroquinolines-based Cxcr4 Antagonmentioning

confidence: 99%

Small Molecule Inhibitors of CXCR4

Debnath¹,

Xu²,

Grande³

et al. 2013

Theranostics

243

199

View full text Add to dashboard Cite

show abstract

“…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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“…inhibitors [289][290][291], including T140 [195] and AMD3100 [275]. expressing neoplastic cells [34][35][36], inhibition by binding and sequestering compounds act at the extracellular surface of CXCR4 including AMD31 00 and T140 which are depicted in Figure 52 .…”

Section: Discussionmentioning

confidence: 99%

“…Modification of the terminal benzene group by addition of electronegative substituents also decreased the anti-CXCR4 activity of the parent compound. EClVS14 is unique in its inability to modify calcium signaling, a characteristic that is not shared by any other CXCR4 inhibitors [289][290][291], including T140 [195] and AMD3100 [275].…”

Section: Discussionmentioning

confidence: 99%

Structure-based design of inhibitors of CXCR4.

Meier¹

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Synthesis and SAR of novel CXCR4 antagonists that are potent inhibitors of T tropic (X4) HIV-1 replication

Cited by 32 publications

References 18 publications

Small Molecule Inhibitors of CXCR4

Small Molecule Inhibitors of CXCR4

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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