Carboxylic acid bioisosteres acylsulfonamides, acylsulfamides, and sulfonylureas as novel antagonists of the CXCR2 receptor

Winters, Michael P.; Crysler, Carl; Subasinghe, Nalin L.; Ryan, Declan; Leong, Lynette; Zhao, Shuyuan; Donatelli, Robert R.; Yurkow, Edward J.; Mazzulla, Marie; Boczon, Lisa; Manthey, Carl L.; Molloy, Christopher J.; Raymond, Holly; Murray, Lynne A.; McAlonan, Laura; Tomczuk, Bruce E.

doi:10.1016/j.bmcl.2008.01.127

Cited by 32 publications

(25 citation statements)

References 17 publications

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“…In contrast, CXCR2 antagonists, like other chemokine receptor antagonists, have demonstrated differences in species crossreactivity [137]. These species differences, that are not uncommon for GPCRs, may likely be a result of the antagonists binding to allosteric sites, which indeed has been shown for a number of CXCR2 ligands [118,124]. Allosteric binding sites need not have evolved to accommodate an endogenous ligand and are thus more likely to show sequence divergence between subtypes and between species.…”

Section: Challenges and Future Perspectivesmentioning

confidence: 98%

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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: Challenges and Future Perspectivesmentioning

confidence: 98%

“…In search of orally bioavailable CXCR2 antagonist, researchers at Johnson & Johnson investigated carboxylic acid bioisosteres of 35, a compound which reportedly is a submicromolar inhibitor of CXCR2 [124]. Most successful proved to be a series of acylsulfonamides as exemplified by compound 36.…”

Section: Indolylbuteric Acid Derivativesmentioning

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%

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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“…Diarylsulfonylureas became widely available since 1955 as popular antidiabetic drugs in clinical practice for the treatment of type 2 diabetes, by virtue of their insulin secretagogue properties. The synthesis of compounds containing diarylsulfonylurea moiety has been a subject of extensive research in the recent past because of their enormous biological activities such as hypoglycemics [4], Vibrio fischeri quorum sensing regulators [5], CXCR2 receptor antagonists [6], antimalarials [7], antibacterials [8], human thromboxane A2 receptor isoforms TPα and TPβ antagonists [9], reversible inhibitors of human steroid sulfatase [10], KATP-channel openers [11], ANG II (AT1) receptor antagonists [12], oncolytics [13], acyl-CoA inhibitors [14], vasodilators [15], aldehyde dehydrogenase inhibitors [16], cancer chemotherapeutics [17], diuretic [18], β3 adrenergic receptor agonists [19], non competitive inhibitors of acetohydroxyacid synthase from Mycobacterium tuberculosis [20], and as peroxisome proliferator activated receptor gamma (PPARγ) agonists [21].…”

Section: Introductionmentioning

confidence: 99%