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Exploratory studies on development of the chemokine receptor CXCR4 antagonists toward downsizing.

Tamamura H, Tsutsumi H, Nomura W, Fujii N - Perspect Medicin Chem (2008)

Bottom Line: Seven transmembrane (7TM) G-protein-coupled receptor (GPCR) families are important targets for drug discovery, and specific antagonists for GPCR can accelerate research in the field of medicinal chemistry.Fourteen-mer peptides, T140 and its analogs, and downsized cyclic pentapeptides have been developed by us as potent CXCR4 antagonists.This article describes the development of a number of specific CXCR4 antagonists in our laboratory, including downsizing.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan.

ABSTRACT
Seven transmembrane (7TM) G-protein-coupled receptor (GPCR) families are important targets for drug discovery, and specific antagonists for GPCR can accelerate research in the field of medicinal chemistry. The chemokine receptor CXCR4 is a GPCR that possesses a unique ligand CXCL12/stromal cell-derived factor-1 (SDF-1). The interaction between CXCL12 and CXCR4 is essential for the migration of progenitor cells during embryonic development of the cardiovascular, hemopoietic and central nervous systems, and also involved in several intractable disease processes, including HIV infection, cancer cell metastasis, progression of acute and chronic leukemias, rheumatoid arthritis and pulmonary fibrosis. Thus, CXCR4 may be an important therapeutic target in all of these diseases, and various CXCR4 antagonists have been proposed as potential drugs. Fourteen-mer peptides, T140 and its analogs, and downsized cyclic pentapeptides have been developed by us as potent CXCR4 antagonists. This article describes the development of a number of specific CXCR4 antagonists in our laboratory, including downsizing.

No MeSH data available.


Related in: MedlinePlus

Structures of a linear type of low molecular weight CXCR4 antagonists.
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f4-pmc-2008-001: Structures of a linear type of low molecular weight CXCR4 antagonists.

Mentions: Identification of a novel pharmacophore for CXCR4 antagonism, such as a 4-fluorobenzoyl or 4-fluorophenyl moiety, prompted us to develop a linear type of low molecular weight CXCR4 antagonists. By combining substructure units of the T140 pharmacophore and new pharmacophore moieties, several compounds were designed and synthesized using combinatorial chemistry. As a result, several linear compounds were found as moderate CXCR4 antagonists, such as compounds 1–3 shown in Figure 4 (Tamamura, Tsutsumi et al. 2006). These compounds are relatively weaker than a cyclic pentapeptide FC131. Thus, it is thought that conformational constriction based on a cyclic pentapeptide scaffold is critical for strong potency.


Exploratory studies on development of the chemokine receptor CXCR4 antagonists toward downsizing.

Tamamura H, Tsutsumi H, Nomura W, Fujii N - Perspect Medicin Chem (2008)

Structures of a linear type of low molecular weight CXCR4 antagonists.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2746577&req=5

f4-pmc-2008-001: Structures of a linear type of low molecular weight CXCR4 antagonists.
Mentions: Identification of a novel pharmacophore for CXCR4 antagonism, such as a 4-fluorobenzoyl or 4-fluorophenyl moiety, prompted us to develop a linear type of low molecular weight CXCR4 antagonists. By combining substructure units of the T140 pharmacophore and new pharmacophore moieties, several compounds were designed and synthesized using combinatorial chemistry. As a result, several linear compounds were found as moderate CXCR4 antagonists, such as compounds 1–3 shown in Figure 4 (Tamamura, Tsutsumi et al. 2006). These compounds are relatively weaker than a cyclic pentapeptide FC131. Thus, it is thought that conformational constriction based on a cyclic pentapeptide scaffold is critical for strong potency.

Bottom Line: Seven transmembrane (7TM) G-protein-coupled receptor (GPCR) families are important targets for drug discovery, and specific antagonists for GPCR can accelerate research in the field of medicinal chemistry.Fourteen-mer peptides, T140 and its analogs, and downsized cyclic pentapeptides have been developed by us as potent CXCR4 antagonists.This article describes the development of a number of specific CXCR4 antagonists in our laboratory, including downsizing.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan.

ABSTRACT
Seven transmembrane (7TM) G-protein-coupled receptor (GPCR) families are important targets for drug discovery, and specific antagonists for GPCR can accelerate research in the field of medicinal chemistry. The chemokine receptor CXCR4 is a GPCR that possesses a unique ligand CXCL12/stromal cell-derived factor-1 (SDF-1). The interaction between CXCL12 and CXCR4 is essential for the migration of progenitor cells during embryonic development of the cardiovascular, hemopoietic and central nervous systems, and also involved in several intractable disease processes, including HIV infection, cancer cell metastasis, progression of acute and chronic leukemias, rheumatoid arthritis and pulmonary fibrosis. Thus, CXCR4 may be an important therapeutic target in all of these diseases, and various CXCR4 antagonists have been proposed as potential drugs. Fourteen-mer peptides, T140 and its analogs, and downsized cyclic pentapeptides have been developed by us as potent CXCR4 antagonists. This article describes the development of a number of specific CXCR4 antagonists in our laboratory, including downsizing.

No MeSH data available.


Related in: MedlinePlus