Synthesis and structure–Activity relationship of 2-amino-3-heteroaryl-quinoxalines as non-peptide, small-Molecule antagonists for interleukin-8 receptor

Li, Jie Jack; Carson, Kenneth G.; Trivedi, Bharat K.; Yue, Wen Song; Ye, Qing; Glynn, Roberta A; Miller, Steven R.; Connor, David T.; Roth, Bruce D.; Luly, Jay R.; Low, J. E.; Heilig, David J; Yang, Wenzhong; Qin, Shixin; Hunt, S. Fraser

doi:10.1016/s0968-0896(03)00399-7

Cited by 46 publications

(25 citation statements)

References 21 publications

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“…In view of their therapeutic potential, the search for CXCR2 antagonists has been extensive and has led to the identification of different classes of CXCR2 antagonist (Li et al, 2003;Widdowson et al, 2004;Baxter et al, 2006;Ho et al, 2006). In our previous publication (de Kruijf et al, 2009), we reported that CXCR2 antagonists of the diarylurea (such as SB265610; see Fig.…”

Section: Discussionmentioning

confidence: 99%

“…These studies indicate that CXCR2 is an interesting drug target. In view of this therapeutic potential, different CXCR2 antagonists are being developed (see, for example, Li et al, 2003;Widdowson et al, 2004;Baxter et al, 2006;Ho et al, 2006). Among them, 2-hydroxy-N,Ndimethyl-3-{2-[[(R)-1-(5-methyl-furan-2-yl)-propyl]amino]-3,4-dioxo-cyclobut-1-enylamino}-benzamide (SCH-527123) and repertaxin are currently in phase II clinical trial (http://www.clinicaltrials.gov/ct2/show/NCT01006616; http://www.clinicaltrials.gov/ct2/show/NCT00224406).…”

Section: Introductionmentioning

confidence: 99%

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Identification of a Novel Allosteric Binding Site in the CXCR2 Chemokine Receptor

Kruijf¹,

Lim

Roumen

et al. 2011

Mol Pharmacol

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We have shown previously that different chemical classes of small-molecule antagonists of the human chemokine CXCR2 receptor interact with distinct binding sites of the receptor. Although an intracellular binding site for diarylurea CXCR2 antagonists, such as N-(2-bromophenyl)-NЈ-(7-cyano-1H-benzotriazol-4-yl)urea (SB265610), and thiazolopyrimidine compounds was recently mapped by mutagenesis studies, we now report on an imidazolylpyrimidine antagonist binding pocket in the transmembrane domain of CXCR2. Using different CXCR2 orthologs, chimeric proteins, site-directed mutagenesis, and in silico modeling, we have elucidated the binding mode of this antagonist. Our in silico-guided mutagenesis studies indicate that the ligand binding cavity for imidazolylpyrimidine compounds in CXCR2 is located between transmembrane (TM) helices 3 (Phe130 3.36 ), 5 (Ser217 5.44 , Phe220 5.47 ), and 6 (Asn268 6.52 , Leu271 6.55 ) and suggest that these antagonists enter CXCR2 via the TM5-TM6 interface. It is noteworthy that the same interface is postulated as the ligand entry channel in the opsin receptor and is occupied by lipid molecules in the recently solved crystal structure of the CXCR4 chemokine receptor, suggesting a general ligand entrance mechanism for nonpolar ligands to G protein-coupled receptors. The identification of a novel allosteric binding cavity in the TM domain of CXCR2, in addition to the previously identified intracellular binding site, shows the diversity in ligand recognition mechanisms by this receptor and offers new opportunities for the structure-based design of small allosteric modulators of CXCR2 in the future.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of a Novel Allosteric Binding Site in the CXCR2 Chemokine Receptor

Kruijf¹,

Lim

Roumen

et al. 2011

Mol Pharmacol

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“…As a consequence, different classes of small CXCR2 antagonists have been developed, including diarylureas, thiazolo-and imidazolylpyrimidines, quinoxalines, nicotinamide N-oxides, indole carboxylic acids, and arylpropionic acids (Cutshall et al, 2001;Barth et al, 2002;Li et al, 2003;Widdowson et al, 2004;Allegretti et al, 2005;Baxter et al, 2006;Ho et al, 2006). In this study, we selected seven different CXCR2 antagonists from the diarylurea, imidazolylpyrimidine, and thiazolopyrimidine class and studied their mechanisms of action at human CXCR2.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, in CXCR2 knockout mice or wild-type mice treated with a CXCR2 antagonist or neutralizing antibody, lung tissue damage and ulcerative colitis are reduced, suggesting that CXCR2 is an important drug target (Buanne et al, 2007). In view of this therapeutic potential, different classes of small CXCR2 antagonist have been developed, including diarylureas (Widdowson et al, 2004), thiazolo-and imidazolylpyrimidines (Baxter et al, 2006;Ho et al, 2006), quinoxalines (Li et al, 2003), nicotinamide N-oxides (Cutshall et al, 2001), indole carboxylic acids (Barth et al, 2002), and arylpropionic acids (Allegretti et al, 2005). So far, most literature describes in vitro data of the different CXCR2 antagonist classes.…”

mentioning

confidence: 99%

Nonpeptidergic Allosteric Antagonists Differentially Bind to the CXCR2 Chemokine Receptor

Kruijf¹,

Heteren²,

Lim³

et al. 2009

J Pharmacol Exp Ther

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The chemokine receptor CXCR2 is involved in different inflammatory diseases, like chronic obstructive pulmonary disease, psoriasis, rheumatoid arthritis, and ulcerative colitis; therefore, it is considered an attractive drug target. Different classes of small CXCR2 antagonists have been developed. In this study, we selected seven CXCR2 antagonists from the diarylurea, imidazolylpyrimide, and thiazolopyrimidine class and studied their mechanisms of action at human CXCR2. All compounds are able to displace 125

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“…Similarly, in anti-inflammatory activity of the quinoxaline B (4) by varying R and R substituents. Compounds B1 and B2 were found to be non-peptide antagonists of the interleukin-8 molecule receptor, which is involved in several inflammatory diseases and cancer [25].…”

Section: Pharmacological Uses Of Quinoxalinesmentioning

confidence: 99%

Synthetic Methods and Exploring Biological Potential of Various Substituted Quinoxalin-2-one Derivatives

2016

European Reviews of Chemical Research

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Substituted quinoxaline have considerable interest in chemistry, biology and pharmacology. Quinoxaline derivatives are capable with variety of biological activities and possess different biological activities, of which the most potent are anti-microbial, analgesic and anti-inflammatory activities. It facilitated the researchers to develop various methods for their synthesis and their applications. In this review represented different methods of synthesis, reactivity and various biological activities of quinoxaline derivatives.Keywords: Quinoxaline, reactivity, biological activities, synthetic methods. IntroductionQuinoxaline and its derivatives are important nitrogen containing heterocyclic compounds of various biologically properties. Quinoxaline and its derivatives are mostly of synthetic origin. Substituted quinoxalines are an important class of benzoheterocycles, which constitute the building blocks of wide range of pharmacologically active compounds having antibacterial [1][2][3][4] [15] activities. The quinoxaline is described as a bioisoster of quinoline, naphthalene, benzothiophene and other aromatic rings such as pyridine and pyrazine. Because of the similarity between some antitubercular drugs and quinoxaline, as well as the presence of the quinoxaline moiety in some broad spectrum antibiotics, it was hoped that quinoxaline analogs would exhibit antitubercular activity [16]. The quinoxaline antibiotics are agents of bicyclic desipeptide antibiotic that have been reported activity against gram-positive bacteria and certain tumors and to inhibit RNA synthesis [17]. Quinoxaline has also been used in reactive dyes and pigments, azo dyes, fluroscein dyes and it also forms a part of certain antibiotics. Quinoxaline m.p. 29-30ºC and is miscible with water. It is weakly basic (pka 0.56) and thus considerably weaker base than the isomeric diazonapthalenes namely cinnoline (pka 2.42), pthalizine (pka 3.47) or quinazoline (pka 1.95). 2-Hydroxy-but not 2-amino quinoxaline exist in tautomeric forms.

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Synthesis and structure–Activity relationship of 2-amino-3-heteroaryl-quinoxalines as non-peptide, small-Molecule antagonists for interleukin-8 receptor

Cited by 46 publications

References 21 publications

Identification of a Novel Allosteric Binding Site in the CXCR2 Chemokine Receptor

Identification of a Novel Allosteric Binding Site in the CXCR2 Chemokine Receptor

Nonpeptidergic Allosteric Antagonists Differentially Bind to the CXCR2 Chemokine Receptor

Synthetic Methods and Exploring Biological Potential of Various Substituted Quinoxalin-2-one Derivatives

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