N -Benzoyl amino acids as ICAM/LFA-1 inhibitors. Part 2: Structure–activity relationship of the benzoyl moiety

Burdick, Daniel J.; Marsters, James C.; Aliagas-Martin, Ignacio; Stanley, Mark; Beresini, Maureen H.; McDowell, Robert S.; Gadek, Thomas R.

doi:10.1016/j.bmcl.2004.02.046

Cited by 12 publications

(5 citation statements)

References 10 publications

(7 reference statements)

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“…This class of small molecules has been shown to exhibit potent activities both in vitro and in vivo. The detailed structure–activity relationships of these antagonists, including the modulation of selectivity for LFA‐1 over the closely related integrin, MAC‐1 (αMβ2; CD11b/ CD18), are the subject of studies reported elsewhere (Keating et al 2000; Gadek et al 2002; Burdick et al 2003, 2004). One of these small molecules, compound 3 (Fig.…”

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confidence: 99%

Competition between intercellular adhesion molecule‐1 and a small‐molecule antagonist for a common binding site on the αl subunit of lymphocyte function‐associated antigen‐1

Keating¹

2006

Protein Science

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The lymphocyte function-associated antigen-1 (LFA-1) binding of a unique class of small-molecule antagonists as represented by compound 3 was analyzed in comparison to that of soluble intercellular adhesion molecule-1 (sICAM-1) and A-286982, which respectively define direct and allosteric competitive binding sites within LFA-1's inserted (I) domain. All three molecules antagonized LFA-1 binding to ICAM-1-Immunoglobulin G fusion (ICAM-1-Ig) in a competition ELISA, but only compound 3 and sICAM-1 inhibited the binding of a fluorescein-labeled analog of compound 3 to LFA-1. Compound 3 and sICAM-1 displayed classical direct competitive binding behavior with ICAM-1. Their antagonism of LFA-1 was surmountable by both ICAM-1-Ig and a fluoresceinlabeled compound 3 analog. The competition of both sICAM-1 and compound 3 with ICAM-1-Ig for LFA-1 resulted in equivalent and linear Schild plots with slopes of 1.24 and 1.26, respectively. Cross-linking studies with a photoactivated analog of compound 3 localized the high-affinity smallmolecule binding site to the N-terminal 507 amino acid segment of the a chain of LFA-1, a region that includes the I domain. In addition, cells transfected with a variant of LFA-1 lacking this I domain showed no significant binding of a fluorescein-labeled analog of compound 3 or ICAM-1-Ig. These results demonstrate that compound 3 inhibits the LFA-1/ICAM-1 binding interaction in a directly competitive manner by binding to a high-affinity site on LFA-1. This binding site overlaps with the ICAM-1 binding site on the a subunit of LFA-1, which has previously been localized to the I domain. Abbreviations: LFA-1, lymphocyte function-associated antigen-1; ICAM-1, intercellular adhesion molecule-1; I domain, inserted domain; MIDAS, metal ion-dependent adhesion site; IDAS, I domain allosteric site; ICAM-1-Ig, ICAM-1-Immunoglobulin G fusion; sICAM-1, soluble ICAM-1; HRP, horseradish peroxidase; FITC, fluorescein isothiocyante; FP, fluorescence polarization; BGG, bovine g globulins; PBS, phosphatebuffered saline; BSA, bovine serum albumin; TMB, tetramethylbenzidine; GuHCl, guanidine hydrochloride; SDS-PAGE, sodium dodecyl sulfatepolyacrylamide gel electrophoresis.Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi

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Competition between intercellular adhesion molecule‐1 and a small‐molecule antagonist for a common binding site on the αl subunit of lymphocyte function‐associated antigen‐1

Keating¹

2006

Protein Science

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“…An initial active compound mimicking E34 and Y66 was isolated with modest LFA-1/ICAM-1 antagonist activity using relatively simple benzoyl amino acid moieties. 54 , 55 Further enhancements were elaborated off the benzoyl moiety to incorporate mimicry of the N68 and Q73 side chains resulting in a ~30-fold improvement in potency and specificity for LFA-1. Eventually, a small set of non-peptide lead compounds was created that satisfied the criteria for LFA-1 binding, but additional optimization was necessary to ultimately identify a tailor-made molecule that could be a commercially viable pharmaceutical for specifically treating DED.…”

Section: Discovery Of Lifitegrastmentioning

confidence: 99%

Development of lifitegrast: a novel T-cell inhibitor for the treatment of dry eye disease

Semba

Gadek²

2016

OPTH

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Dry eye disease (DED) is a multifactorial disorder of the ocular surface characterized by symptoms of discomfort, decreased tear quality, and chronic inflammation that affects an estimated 20 million patients in the US alone. DED is associated with localized inflammation of the ocular surface and periocular tissues leading to homing and activation of T cells, cytokine release, and development of hyperosmolar tears. This inflammatory milieu results in symptoms of eye dryness and discomfort. Homing of T cells to the ocular surface is influenced by the binding of lymphocyte function-associated antigen-1 (LFA-1; CD11a/CD18; αLβ2), a cell surface adhesion protein, to its cognate ligand, intercellular adhesion molecule-1 (ICAM-1; CD54), which is expressed on inflamed ocular/periocular epithelium and vascular endothelium. LFA-1/ICAM-1 binding within the immunologic synapse enables both T-cell activation and cytokine release. Lifitegrast is a novel T-cell integrin antagonist that is designed to mimic the binding epitope of ICAM-1. It serves as a molecular decoy to block the binding of LFA-1/ICAM-1 and inhibits the downstream inflammatory process. In vitro studies have demonstrated that lifitegrast inhibits T-cell adhesion to ICAM-1-expressing cells and inhibits secretion of pro-inflammatory cytokines including interferon gamma, tumor necrosis factor alpha, macrophage inflammatory protein 1 alpha, interleukin (IL)-1α, IL-1β, IL-2, IL-4, and IL-6, all of which are known to be associated with DED. Lifitegrast has the potential to be the first pharmaceutical product approved in the US indicated for the treatment of both symptoms and signs of DED. Clinical trials involving over 2,500 adult DED patients have demonstrated that topically administered lifitegrast 5.0% ophthalmic solution can rapidly reduce the symptoms of eye dryness and decrease ocular surface staining with an acceptable long-term safety profile. The purpose of this review is to highlight the developmental story – from bench top to bedside – behind the scientific rationale, engineering, and clinical experience of lifitegrast for the treatment of DED.

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“…On the basis of experience previously acquired with the design of RGD (Arg-Gly-Asp) peptidomimetics, this approach yielded a cyclic peptide lead to an LFA-1 antagonist with micromolar IC 50 values The pharmacophoric points of this peptide were subsequently mimicked on an N-benzoyl-substituted tryptophan scaffold and optimized using a modular approach (Burdick et al 2003(Burdick et al , 2004. This class of LFA-1 antagonists compete with nanomolar affinity with ICAM-1 for a common binding site in the I-domain of the alpha subunit of LFA-1 (Keating et al 2006) and are mechanistically distinct from allosteric LFA-1 antagonists discovered by other organizations (Liu et al 2000).…”

Section: Introductionmentioning

confidence: 99%

Preclinical absorption, distribution, metabolism and excretion (ADME) characterization of ICAM1988, an LFA-1/ICAM antagonist, and its prodrug

Khojasteh¹,

Leipold²,

Lai

et al. 2008

Xenobiotica

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1) Intercellular adhesion molecule (ICAM)-1988 is a small molecule lymphocyte functionassociated antigen-1 (LFA-1) antagonist being considered for its anti-inflammatory properties. Following intravenous administration of ICAM1988, clearances in mice, rats, dogs, and monkeys were 17.8, 3.31, 15.4, and 6.85 ml min À1 kg À1 , respectively.(2) In mass balance studies using [ 14 C]-ICAM1988 in rats dosed intravenously, unchanged ICAM1988 contributed to 25.1% of the dose. (3) In rats, the systemic bioavailability of ICAM1988 was improved to 0.28 when the drug was administered orally as its isobutyl ester, ICAM2660. In rats, this was consistent with the complete in vitro conversion of ICAM2660 to ICAM1988 in plasma, and liver and intestinal S9. (4) In dogs and monkeys, ICAM2660 did not improve the bioavailability of ICAM1988. This is consistent with limited in vitro conversion of ICAM2660 to ICAM1988 in plasma and liver S9. (5) In human in vitro studies, ICAM2660 conversion to ICAM1988 in liver was similar to rats while no conversion in plasma and intestinal S9 fractions were observed. Based on the in vitro metabolism similarities of human and rat, it would be anticipated that in human oral administration of ICAM2660 would improve the systemic exposure of ICAM1988.

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N -Benzoyl amino acids as ICAM/LFA-1 inhibitors. Part 2: Structure–activity relationship of the benzoyl moiety

Cited by 12 publications

References 10 publications

Competition between intercellular adhesion molecule‐1 and a small‐molecule antagonist for a common binding site on the αl subunit of lymphocyte function‐associated antigen‐1

Competition between intercellular adhesion molecule‐1 and a small‐molecule antagonist for a common binding site on the αl subunit of lymphocyte function‐associated antigen‐1

Development of lifitegrast: a novel T-cell inhibitor for the treatment of dry eye disease

Preclinical absorption, distribution, metabolism and excretion (ADME) characterization of ICAM1988, an LFA-1/ICAM antagonist, and its prodrug

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