Nicotinanilides as inhibitors of neutrophil chemotaxis

Cutshall, Neil S.; Kucera, Kristin A.; Ursino, Rocky; Latham, John; Ihle, Nathan C.

doi:10.1016/s0960-894x(02)00188-9

Cited by 31 publications

(16 citation statements)

References 7 publications

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“…The equipotent but oxygen-containing nicotinamide glycolates 3 and 4 exhibited a similar activity profile in cell-free assays of 125 I-CXCL8 and 125 I-CXCL1 binding to CXCR2 membranes, and in whole-cell assays of CXCL1-mediated chemotaxis and calcium flux. Absent antagonism at N-formyl peptide receptors CCR1, CCR2, CCR3, and CCR9 supported the CXCR2-selectivity of compounds 1 to 4 (Cutshall et al, 2002). The structure-activity relationship of 1 and 2 in cell-free assays indicated that methyl esterification of the carboxylic acid was a sufficient perturbation to render 2 inactive at CXCR2.…”

Section: Resultsmentioning

confidence: 80%

“…All reagents and solvents were used as received. Compounds 1 to 4 were prepared as described by Cutshall et al (2002), and synthetic methods and characterization of compounds 5 and 6 are detailed in the supplemental data. To prepare the tritiated derivatives of 3 and 4 (Fig.…”

Section: Methodsmentioning

confidence: 99%

“…1). Although a representative nicotinamide glycolate methyl ester 1 of this class was shown to potently antagonize CXCL1-mediated chemotaxis of primary human PMNs in vitro, with an IC 50 of 42 nM (Cutshall et al, 2002), pharmacological mechanisms were not evaluated. Through the use of tritiated derivatives and direct electroporation of compounds into PMNs, we show that the methyl ester form (e.g., 3) permeates through the PMN cell membrane, is rapidly hydrolyzed to the nicotinamide glycolate acid (e.g., 4), and then accumulates intracellularly to millimolar concentrations, where it acts as a CXCR2 antagonist.…”

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confidence: 99%

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Nicotinamide Glycolates Antagonize CXCR2 Activity through an Intracellular Mechanism

Maeda¹,

Quinn²,

Schepetkin³

et al. 2009

J Pharmacol Exp Ther

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The chemokine receptors CXCR1/2 are involved in a variety of inflammatory diseases, including chronic obstructive pulmonary disease. Several classes of allosteric small-molecule CXCR1/2 antagonists have been developed. The data presented here describe the cellular pharmacology of the acid and ester forms of the nicotinamide glycolate pharmacophore, a potent antagonist of CXCR2 signaling by the chemokines CXCL1 and CXCL8. H acid was not internalized by neutrophils but was sufficient alone to inhibit CXCL1-stimulated calcium flux in neutrophils that were permeabilized by electroporation to permit its direct access to the cell interior. Neutrophil efflux of the acid was probenecid-sensitive, consistent with an organic acid transporter. These data support a mechanism wherein the nicotinamide glycolate ester serves as a lipophilic precursor that efficiently translocates into the intracellular neutrophil space to liberate the active acid form of the pharmacophore, which then acts at an intracellular site. Rapid inactivation by plasma esterases precluded use in vivo, but the mechanism elucidated provided insight for new nicotinamide pharmacophore classes with therapeutic potential.Chemoattractant cytokines, or chemokines, promote the directed migration of polymorphonuclear leukocytes (PMNs) to sites of inflammation in a process known as chemotaxis. Among the most important chemokines released during inflammatory responses are the "Cys-XaaCys" (CXC) or ␣ chemokines, which are characterized by the presence of an intervening amino acid between con-

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Section: Resultsmentioning

confidence: 80%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Nicotinamide Glycolates Antagonize CXCR2 Activity through an Intracellular Mechanism

Maeda¹,

Quinn²,

Schepetkin³

et al. 2009

J Pharmacol Exp Ther

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“…29,30) Hence the synthesis of polysubstituted piperidones and pyridines is a topic of current interest. 31,32) This prompted us to perform the synthesis of poly substituted piperidines and pyridines and probe their biological potential.…”

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confidence: 99%

A Facile Synthesis and Discovery of Highly Functionalized Tetrahydro-pyridines and Pyridines as Antimycobacterial Agents

Kumar

Rajesh

Perumal

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Further SAR studies showed that thioglycolate esters, like 42, displayed improved inhibition of chemotaxis (42: IC 50 42 nM) but were, like 40, unable to block [ 125 I]-CXCL8 binding[128].…”

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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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Nicotinanilides as inhibitors of neutrophil chemotaxis

Cited by 31 publications

References 7 publications

Nicotinamide Glycolates Antagonize CXCR2 Activity through an Intracellular Mechanism

Nicotinamide Glycolates Antagonize CXCR2 Activity through an Intracellular Mechanism

A Facile Synthesis and Discovery of Highly Functionalized Tetrahydro-pyridines and Pyridines as Antimycobacterial Agents

Low Molecular Weight CXCR2 Antagonists as Promising Therapeutics

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