Synthesis and structure–activity relationships of new disubstituted phenyl-containing 3,4-diamino-3-cyclobutene-1,2-diones as CXCR2 receptor antagonists

Lai, Gaifa; Merritt, J. Robert; Zhenmin, He; Feng, Donghai; Chao, Jianhua; Czarniecki, Michael; Rokosz, Laura L.; Stauffer, Tara M.; Rindgen, Diane; Taveras, Arthur G.

doi:10.1016/j.bmcl.2008.02.010

Cited by 10 publications

(10 citation statements)

References 22 publications

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“…Subsequent bioisosteric replacement of the RHS phenyl ring with a 5-methyl substituted 2-furyl motif yielded 20 (SCH 527123) with excellent CXCR2 and CXCR1 potencies ([ 125 I]-CXCL8 IC 50 CXCR2 2.6 nM, CXCR1 36 nM) and vastly improved rat plasma levels after oral administration (AUC 49 mM h). Alternatively, appropriate di-substitution of the RHS phenyl ring of 19 afforded potent compounds, for instance 21, exhibiting equally good oral PK profiles as 20 [111]. Additional binding experiments using [ 3 H]SCH 527123 confirmed the high CXCR1 affinity of SCH 527123 (K d 3.9 nM) but also showed that this compound is effectively a CXCR2-selective binder (K d 0.049 nM) [112].…”

Section: Urea Isosteresmentioning

confidence: 77%

Low Molecular Weight CXCR2 Antagonists as Promising Therapeutics

Mihara¹,

Wijkmans²

2010

Methods and Principles in Medicinal Chemistry

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The chemokine receptor CXCR2 recognizes endogenous chemokines that possess a N-terminal Glu-Leu-Arg (ELR) þ amino acid sequence immediately adjacent to their CXC motif. CXCR2 and the closely related receptor CXCR1 are expressed on the cellular surface of leukocytes, notably neutrophils, endothelial cells and a range of other cell types throughout the human body. It has been firmly established now that CXCR2 plays a critical role in the development of numerous inflammatory disorders, wound healing and tumor progression [1-5]. As classically defined for chemokine receptors, CXCR2 mediates cell migration but has also been recognized as a key angiogenic factor [6,7]. These multifunctional roles have drawn increased attention to CXCR2 as a potentially successful drug target for therapeutic intervention in a range of diseases. The first half of this chapter summarizes the biological role of CXCR2 and its involvement, particularly in inflammatory disorders, in order to illuminate the potential clinical impact and relevance of CXCR2 blocking strategies. A review of all currently known low molecular weight (LMW) CXCR2 antagonists is addressed in the second half of this chapter. CXCR2 Ligands and Signal TransductionCXCR2, which shows 78% overall amino acid identity with CXCR1, was first cloned in 1991 out of human promyelocytic leukemia HL60 cells [8]. Subsequent research demonstrated that CXCR2 is the cognate receptor for at least seven structurally related (ELR) þ chemokines, which are growth-related protein (Gro)-a, -b and -c (CXCL1-CXCL3), epithelium-derived neutrophil attractant-78 (ENA-78; CXCL5), granulocyte chemotactic protein-2 (GCP-2; CXCL6), neutrophil-activating peptide-2 (NAP-2; CXCL7) and interleukin-8 (IL-8; CXCL8) [9, 10]. In contrast,

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Section: Urea Isosteresmentioning

confidence: 77%

Low Molecular Weight CXCR2 Antagonists as Promising Therapeutics

Mihara¹,

Wijkmans²

2010

Methods and Principles in Medicinal Chemistry

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“…In 2008 Lai et al [60] focused their study on non-furyl diaminocyclobutenediones and investigated the efficacy of disubstituted phenyl-containing 3,4-diamino-3-cyclobutene-1,2-diones as potent CXCR2 receptor antagonists. The CXCR2 binding data K i given in Table 15 …”

Section: Phenyl-containing 34-diamino-3-cyclobutene-12-dionesmentioning

confidence: 99%

“…Based on the K i data for the CXCR2 receptor (Table 16) we obtained Equation 21: Table 15. Structures, biological data [60] and physiochemical parameters used to obtain Equation (20). No role for lipophilicity was found.…”

Section: Diaminocyclobutenedionesmentioning

confidence: 99%

“…IL-8 binding to the receptors causes calcium flux [54], degranulation [55] and chemotaxis [56]. Several classes of compounds ( Figure 3) have been investigated for their ability to act as interleukin-8 receptor antagonists (CXCR1/2 antagonists), including 2-amino-3-heteroaryl quinoxalines [57], imidazolylpyrimidines [58], 3-arylamino-2H-1,2,4-benzothiadiazin-5-ol 1,1-dioxides [59], various derivatives of diaminocyclobutenedione [60][61][62][63][64][65][66][67], thiazolo [4,5-d]pyrimidines [68,69], 3,4-diamino-1,2,5-thiadiazoles [70], 3,4-diamino-2,5-thiazole-1-oxides [71], phenylacetic derivatives [72], N,N'-diarylcyanoguanidines [73], carboxylic acid bioisosteres (acylsulfonamides, acylsulfamides and sulfonylureas) [74], N,N'-diarylureas [75], 3,5-diarylisoxazoles and 3,5-diaryl-1,2,4-oxadiazoles [76], N,N'-diarylsquaramides and N,N'-diarylureas [77], nicotinamide N-oxides [78], triazolethiol [79] and 2-arylpropionic ligands [80].…”

Section: Introductionmentioning

confidence: 99%

“…Binding assays for CXCR2 receptor antagonists include: membranes prepared from Chinese hamster ovary (CHO) cells (cells) transfected with human CXCR2 receptor and labelled IL-8 [58,59,73], the CXCR2 scintillation proximity assay (SPA) [60,64,68], the DELFIA (dissociation-enhanced lanthanide fluorescent immunoassay) binding assay [74] and competition binding assays at hCXCR1/2 [61]. For CXCR1 antagonists the CXCL8-induced hPMN chemotaxis assay was used [72].…”

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Cytokines in terms of QSAR. Review, evaluation and comparative studies

Konstantinidou

Hadjipavlou‐Litina

2013

SAR and QSAR in Environmental Research

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Cytokines represent a class of chemical factors that act as mediators in the complex biological response of inflammation, potentially implicated in various diseases. Therefore, selective inhibition or antagonism of cytokines is a target of anti-inflammatory drug design. The QSAR (Quantitative Structure-Activity Relationships) analysis presented here attempts to identify the structural features and physicochemical properties that are significant for cytokine antagonists or inhibitors and in particular of i) interleukin-5 (IL-5), ii) interleukin-6 (IL-6) and iii) of the chemotactic cytokine (chemokine) interleukin-8 (IL-8). Firstly, a historical aspect of the limited published QSARs is discussed and then a 2D-QSAR analysis was carried out for 26 data sets of compounds using the C-QSAR program of Biobyte. In six cases hydrophobicity appeared to be important. Steric factors in the form of overall molar refractivity (CMR), molar refractivity of the substituent (MR), molar volume (MgVol), Taft's Es constant and the sterimol parameters B1 and B5 have a significant impact on biological activity in most of the derived equations whereas electronic parameters as σp, σm or Σσ appeared in five cases.

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Bacterial Proteins against Metastasis

Walenkamp

2010

Emerging Cancer Therapy

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Synthesis and structure–activity relationships of new disubstituted phenyl-containing 3,4-diamino-3-cyclobutene-1,2-diones as CXCR2 receptor antagonists

Cited by 10 publications

References 22 publications

Low Molecular Weight CXCR2 Antagonists as Promising Therapeutics

Low Molecular Weight CXCR2 Antagonists as Promising Therapeutics

Cytokines in terms of QSAR. Review, evaluation and comparative studies

Bacterial Proteins against Metastasis

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