SAR studies on thiazolo[4,5-d]pyrimidine based CXCR2 antagonists involving a novel tandem displacement reaction

Hunt, Fraser; Austin, Caroline A.; Austin, Rupert P.; Bonnert, Roger V.; Cage, Peter; Christie, Jadeen; Christie, Mark; Dixon, Clare; Hill, Steven M.; Jewell, R. A.; Martin, Ian L.; Robinson, David; Willis, Paul

doi:10.1016/j.bmcl.2007.02.080

Cited by 30 publications

(17 citation statements)

References 8 publications

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“…Minor but subtle modification of these groups led to the discovery of lead compound 27, which showed high in vitro potencies ([ 125 I]-CXCL8 IC 50 14 nM, Ca 2 þ IC 50 40 nM) but only moderate oral bioavailability in rat (F 15%). Subsequent potency-driven optimization furnished chiral thiazolopyrimidine 28 with 10-fold improved CXCR2 affinity ([ 125 I]-CXCL8 IC 50 4 nM) [119]. Unfortunately, oral bioavailability in rat was again rather low (F 9%).…”

Section: Thiazolopyrimidinesmentioning

confidence: 99%

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: Thiazolopyrimidinesmentioning

confidence: 99%

Low Molecular Weight CXCR2 Antagonists as Promising Therapeutics

Mihara¹,

Wijkmans²

2010

Methods and Principles in Medicinal Chemistry

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“…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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“…Thiazolo [4,5-d]pyrimidines can be prepared either from thiouramil by using formic acid and some anhydrides followed by phosphorus oxychloride oxidation or from onepot reaction of 4,6-dichloro-5-aminopyrimidine with isothiocyanates in the presence of solid-phase transfer catalysts or through the transformation of 6-aminothiouracil in a stepwise manner [19][20][21][22][23]. Besides, some fluorinated spiro-and iminothioxo-analogs can be prepared by the reaction of spirothiazolidines with thiourea and 2-aminopyridines under microwave irradiation conditions and by the reaction of imino-ethers with semicarbazide or furoic acid hydrazides, respectively [24,25].…”

Section: Introductionmentioning

confidence: 99%