Diaminocyclobutenediones as potent and orally bioavailable CXCR2 receptor antagonists: SAR in the phenolic amide region

Aki, Cynthia; Chao, Jianping; Ferreira, Johan A.; Dwyer, Michael P.; Yu, Younong; Chao, Jianhua; Merritt, Robert J.; Lai, Gaifa; Wu, Minglang; Hipkin, R. William; Fan, Xuerong; Gonsiorek, Waldemar; Fosseta, James; Rindgen, Diane; Fine, Jay S.; Lundell, Daniel; Taveras, Arthur G.; Biju, Purakkattle

doi:10.1016/j.bmcl.2009.05.049

Cited by 9 publications

(12 citation statements)

References 32 publications

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“…Biju et al [61], trying to establish structure-activity relationships of 3,4-diaminocyclobutenediones as CXCR2 receptor antagonists, modified the left phenolic amide region. Based on the K i data for the CXCR2 receptor (Table 16) we obtained Equation 21: Table 15.…”

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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confidence: 99%

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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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Section: Diaminocyclobutenedionesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Biological and chemical data of 56 CXCR2 antagonists, taken from the literature (9,10) were selected for the QSAR study. The half maximal inhibitory concentration is a measure of the effectiveness of a compound in inhibiting a biological or biochemical function, which is usually represented as IC 50 in mmol L -1 .…”

Section: Data Setmentioning

confidence: 99%

Structural investigations of CXCR2 receptor antagonists by CoMFA, CoMSIA and flexible docking studies

Gunda¹,

Anugolu²,

Tata³

et al. 2012

Acta Pharmaceutica

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Three-dimensional quantitative structure activity relationship (3D QSAR) analysis was carried out on a set of 56 N,N '-diarylsquaramides, N,N'-diarylureas and diaminocyclobutenediones in order to understand their antagonistic activities against CXCR2. The studies included comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Models with good predictive abilities were generated with CoMFA q 2 = 0.709, r 2 (non-cross-validated square of correlation coefficient) = 0.951, F value = 139.903, r 2 bs = 0.978 with five components, standard error of estimate = 0.144 and the CoMSIA q 2 = 0.592, r 2 = 0.955, F value = 122.399, r 2 bs = 0.973 with six components, standard error of estimate = 0.141. In addition, a homology model of CXCR2 was used for docking based alignment of the compounds. The most active compound then served as a template for alignment of the remaining structures. Further, mapping of contours onto the active site validated each other in terms of residues involved with reference to the respective contours. This integrated molecular docking based alignment followed by 3D QSAR studies provided a further insight to support the structure-based design of CXCR2 antagonistic agents with improved activity profiles. Furthermore, in silico screening was adapted to the QSAR model in order to predict the structures of new, potentially active compounds.

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“…β-Lactam derivatives display interesting biological activities such as CXCR2 receptor potent antagonists, antimicrobial, antitubercular and anti-HCMV activities. [8][9][10][11][12][13] As a consequence, the interest of organic chemists in the synthesis of new β-lactam derivatives remains high.…”

Section: Introductionmentioning

confidence: 99%