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Article ; Online: IL-12 and IL-23 in health and disease.

Stetsko, Dawn / Sauder, Daniel N

2008 Volume 4, Issue 3, Page(s) 301–303

Language	English
Publishing date	2008-05
Publishing country	England
Document type	Editorial
ZDB-ID	2274260-8
ISSN	1744-8409 ; 1744-666X
ISSN (online)	1744-8409
ISSN	1744-666X
DOI	10.1586/1744666X.4.3.301
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Article: Abatacept modulates human dendritic cell-stimulated T-cell proliferation and effector function independent of IDO induction.

Davis, Patricia M / Nadler, Steven G / Stetsko, Dawn K / Suchard, Suzanne J

Clinical immunology (Orlando, Fla.)

2008 Volume 126, Issue 1, Page(s) 38–47

Abstract: Abatacept, the first in a new class of agents for RA, modulates CD28-mediated T-cell costimulation. Abatacept was evaluated for its ability to regulate human T-cell proliferation and cytokine production initiated by dendritic cells. Abatacept reduced T- ... ...

Abstract	Abatacept, the first in a new class of agents for RA, modulates CD28-mediated T-cell costimulation. Abatacept was evaluated for its ability to regulate human T-cell proliferation and cytokine production initiated by dendritic cells. Abatacept reduced T-cell proliferation by >95% at concentrations between 0.3 and 3 microg/ml. The effect of abatacept on T-cell proliferation was not through induction of IDO activity, as no increase in IDO mRNA or kynurenine was observed and 1-methyl-D-tryptophan did not reverse the inhibition. In addition to the effect of abatacept on proliferation, T-cell cytokines, IL-2, TNFalpha and IFNgamma were also reduced. Abatacept also inhibited proliferation and cytokine production in a T-cell memory response. These data demonstrate that abatacept, independent of IDO activity, attenuates both naive and memory T-cell proliferation and effector function. Taken together, these data aid our understanding of the mechanism for efficacy of abatacept in patients with autoimmune disease.
MeSH term(s)	Abatacept ; Cell Proliferation ; Cytokines/immunology ; Cytokines/metabolism ; Dendritic Cells/drug effects ; Dendritic Cells/enzymology ; Dendritic Cells/immunology ; Humans ; Immunoconjugates/pharmacology ; Immunologic Memory ; Immunosuppressive Agents/pharmacology ; Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism ; Kynurenine/metabolism ; Lymphocyte Activation/immunology ; Lymphocyte Culture Test, Mixed ; RNA, Messenger/metabolism ; T-Lymphocyte Subsets/immunology ; Tetanus Toxoid/immunology
Chemical Substances	Cytokines ; Immunoconjugates ; Immunosuppressive Agents ; Indoleamine-Pyrrole 2,3,-Dioxygenase ; RNA, Messenger ; Tetanus Toxoid ; Kynurenine (343-65-7) ; Abatacept (7D0YB67S97)
Language	English
Publishing date	2008-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1459903-x
ISSN	1521-7035 ; 1521-6616
ISSN (online)	1521-7035
ISSN	1521-6616
DOI	10.1016/j.clim.2007.08.019
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Article: B cells from African American lupus patients exhibit an activated phenotype.

Menard, Laurence C / Habte, Sium / Gonsiorek, Waldemar / Lee, Deborah / Banas, Dana / Holloway, Deborah A / Manjarrez-Orduno, Nataly / Cunningham, Mark / Stetsko, Dawn / Casano, Francesca / Kansal, Selena / Davis, Patricia M / Carman, Julie / Zhang, Clarence K / Abidi, Ferva / Furie, Richard / Nadler, Steven G / Suchard, Suzanne J

JCI insight

2016 Volume 1, Issue 9, Page(s) e87310

Abstract: Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease driven by both innate and adaptive immune cells. African Americans tend to present with more severe disease at an earlier age compared with patients of European ancestry. In ... ...

Abstract	Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease driven by both innate and adaptive immune cells. African Americans tend to present with more severe disease at an earlier age compared with patients of European ancestry. In order to better understand the immunological differences between African American and European American patients, we analyzed the frequencies of B cell subsets and the expression of B cell activation markers from a total of 68 SLE patients and 69 normal healthy volunteers. We found that B cells expressing the activation markers CD86, CD80, PD1, and CD40L, as well as CD19
MeSH term(s)	African Americans ; Antigens, Surface/analysis ; B-Lymphocytes/cytology ; B7-2 Antigen/analysis ; CD40 Antigens/analysis ; CD40 Ligand/analysis ; Humans ; Lupus Erythematosus, Systemic/ethnology ; Phenotype
Chemical Substances	Antigens, Surface ; B7-2 Antigen ; CD40 Antigens ; CD40 Ligand (147205-72-9)
Language	English
Publishing date	2016-06-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN	2379-3708
DOI	10.1172/jci.insight.87310
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Article ; Online: 2B4 (CD244) induced by selective CD28 blockade functionally regulates allograft-specific CD8+ T cell responses.

Liu, Danya / Krummey, Scott M / Badell, I Raul / Wagener, Maylene / Schneeweis, Lumelle A / Stetsko, Dawn K / Suchard, Suzanne J / Nadler, Steven G / Ford, Mandy L

The Journal of experimental medicine

2014 Volume 211, Issue 2, Page(s) 297–311

Abstract: Mounting evidence in models of both autoimmunity and chronic viral infection suggests that the outcome of T cell activation is critically impacted by the constellation of co-stimulatory and co-inhibitory receptors expressed on the cell surface. Here, we ... ...

Abstract	Mounting evidence in models of both autoimmunity and chronic viral infection suggests that the outcome of T cell activation is critically impacted by the constellation of co-stimulatory and co-inhibitory receptors expressed on the cell surface. Here, we identified a critical role for the co-inhibitory SLAM family member 2B4 (CD244) in attenuating primary antigen-specific CD8(+) T cell responses in the presence of immune modulation with selective CD28 blockade. Our results reveal a specific up-regulation of 2B4 on antigen-specific CD8(+) T cells in animals in which CD28 signaling was blocked. However, 2B4 up-regulation was not observed in animals treated with CTLA-4 Ig (abatacept) or CD28 blockade in the presence of anti-CTLA-4 mAb. 2B4 up-regulation after CD28 blockade was functionally significant, as the inhibitory impact of CD28 blockade was diminished when antigen-specific CD8(+) T cells were deficient in 2B4. In contrast, 2B4 deficiency had no effect on CD8(+) T cell responses during unmodified rejection or in the presence of CTLA-4 Ig. We conclude that blockade of CD28 signals in the presence of preserved CTLA-4 signals results in the unique up-regulation of 2B4 on primary CD8(+) effectors, and that this 2B4 expression plays a critical functional role in controlling antigen-specific CD8(+) T cell responses.
MeSH term(s)	Abatacept ; Allografts ; Animals ; Antibodies, Monoclonal/administration & dosage ; Antigens, CD/biosynthesis ; Antigens, CD/genetics ; B7-H1 Antigen/metabolism ; CD28 Antigens/antagonists & inhibitors ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; CTLA-4 Antigen/antagonists & inhibitors ; Graft Survival/immunology ; Immunoconjugates/administration & dosage ; Inducible T-Cell Co-Stimulator Protein/metabolism ; Lymphocyte Activation ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Models, Immunological ; Receptors, Immunologic/biosynthesis ; Receptors, Immunologic/deficiency ; Receptors, Immunologic/genetics ; Signal Transduction/immunology ; Signaling Lymphocytic Activation Molecule Family ; Skin Transplantation ; Up-Regulation
Chemical Substances	Antibodies, Monoclonal ; Antigens, CD ; B7-H1 Antigen ; CD28 Antigens ; CTLA-4 Antigen ; Cd244a protein, mouse ; Cd274 protein, mouse ; Icos protein, mouse ; Immunoconjugates ; Inducible T-Cell Co-Stimulator Protein ; Receptors, Immunologic ; Signaling Lymphocytic Activation Molecule Family ; Abatacept (7D0YB67S97)
Language	English
Publishing date	2014-02-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20130902
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Article ; Online: Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing Activity.

Dudhgaonkar, Shailesh / Ranade, Sourabh / Nagar, Jignesh / Subramani, Siva / Prasad, Durga Shiv / Karunanithi, Preethi / Srivastava, Ratika / Venkatesh, Kamala / Selvam, Sabariya / Krishnamurthy, Prasad / Mariappan, T Thanga / Saxena, Ajay / Fan, Li / Stetsko, Dawn K / Holloway, Deborah A / Li, Xin / Zhu, Jun / Yang, Wen-Pin / Ruepp, Stefan /

Nair, Satheesh / Santella, Joseph / Duncia, John / Hynes, John / McIntyre, Kim W / Carman, Julie A

Journal of immunology (Baltimore, Md. : 1950)

2016 Volume 198, Issue 3, Page(s) 1308–1319

Abstract: The serine/threonine kinase IL-1R-associated kinase (IRAK)4 is a critical regulator of innate immunity. We have identified BMS-986126, a potent, highly selective inhibitor of IRAK4 kinase activity that demonstrates equipotent activity against multiple ... ...

Abstract	The serine/threonine kinase IL-1R-associated kinase (IRAK)4 is a critical regulator of innate immunity. We have identified BMS-986126, a potent, highly selective inhibitor of IRAK4 kinase activity that demonstrates equipotent activity against multiple MyD88-dependent responses both in vitro and in vivo. BMS-986126 failed to inhibit assays downstream of MyD88-independent receptors, including the TNF receptor and TLR3. Very little activity was seen downstream of TLR4, which can also activate an MyD88-independent pathway. In mice, the compound inhibited cytokine production induced by injection of several different TLR agonists, including those for TLR2, TLR7, and TLR9. The compound also significantly suppressed skin inflammation induced by topical administration of the TLR7 agonist imiquimod. BMS-986126 demonstrated robust activity in the MRL/lpr and NZB/NZW models of lupus, inhibiting multiple pathogenic responses. In the MRL/lpr model, robust activity was observed with the combination of suboptimal doses of BMS-986126 and prednisolone, suggesting the potential for steroid sparing activity. BMS-986126 also demonstrated synergy with prednisolone in assays of TLR7- and TLR9-induced IFN target gene expression using human PBMCs. Lastly, BMS-986126 inhibited TLR7- and TLR9-dependent responses using cells derived from lupus patients, suggesting that inhibition of IRAK4 has the potential for therapeutic benefit in treating lupus.
MeSH term(s)	Animals ; Disease Models, Animal ; Female ; Humans ; Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors ; Lupus Erythematosus, Systemic/drug therapy ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Myeloid Differentiation Factor 88/physiology ; Prednisolone/therapeutic use ; Toll-Like Receptor 7/physiology ; Toll-Like Receptor 9/physiology
Chemical Substances	Myeloid Differentiation Factor 88 ; Toll-Like Receptor 7 ; Toll-Like Receptor 9 ; Prednisolone (9PHQ9Y1OLM) ; IRAK4 protein, human (EC 2.7.11.1) ; Interleukin-1 Receptor-Associated Kinases (EC 2.7.11.1)
Language	English
Publishing date	2016-12-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1600583
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Article ; Online: A monovalent anti-human CD28 domain antibody antagonist: preclinical efficacy and safety.

Suchard, Suzanne J / Davis, Patricia M / Kansal, Selena / Stetsko, Dawn K / Brosius, Ruth / Tamura, James / Schneeweis, Lumelle / Bryson, James / Salcedo, Theodora / Wang, Haiqing / Yang, Zheng / Fleener, Catherine A / Ignatovich, Olga / Plummer, Christopher / Grant, Steven / Nadler, Steven G

Journal of immunology (Baltimore, Md. : 1950)

2013 Volume 191, Issue 9, Page(s) 4599–4610

Abstract: Targeting the CD28-CD80/86 pathway with an anti-CD28 antagonist is a promising alternative to current therapies for autoimmunity. However, attempts at generating conventional anti-CD28 mAbs lacking stimulatory activity has been challenging. In this study, ...

Abstract	Targeting the CD28-CD80/86 pathway with an anti-CD28 antagonist is a promising alternative to current therapies for autoimmunity. However, attempts at generating conventional anti-CD28 mAbs lacking stimulatory activity has been challenging. In this study, we describe anti-human CD28 receptor antagonist domain Abs (dAbs) that are specific for human CD28. These dAbs are potent inhibitors of T cell activation, with an EC50 of 35 ± 14 ng/ml for inhibition of proliferation. The EC50 of 53 ± 11 ng/ml in an ex vivo CD28 receptor occupancy assay corresponds with in vitro functional activity, suggesting a direct correlation. The anti-CD28 dAb is equipotent in the inhibition of CD80- and CD86-mediated T cell proliferation and does not interfere with CTLA-4-mediated downmodulation of CD86 expression on APCs. The anti-CD28 dAbs are monomeric and do not demonstrate any evidence of agonism or costimulatory activity. In cynomolgus monkeys, the anti-CD28 dAb demonstrated pharmacodynamic activity, as measured by the inhibition of a T cell-dependent Ab response, without evidence of T cell depletion or cytokine release. Furthermore, there was a strong correlation between systemic exposure, duration, and extent of CD28 receptor occupancy, and pharmacodynamic activity. Taken together, these data support clinical evaluation of this novel anti-CD28 dAb for the treatment of autoimmune diseases.
MeSH term(s)	Animals ; Antibodies/immunology ; Antigen-Presenting Cells/immunology ; Autoimmune Diseases/therapy ; B7-1 Antigen/immunology ; B7-2 Antigen/immunology ; CD28 Antigens/antagonists & inhibitors ; CD28 Antigens/immunology ; CTLA-4 Antigen/immunology ; Cell Proliferation ; Humans ; Lymphocyte Activation/immunology ; Macaca fascicularis ; T-Lymphocytes/immunology
Chemical Substances	Antibodies ; B7-1 Antigen ; B7-2 Antigen ; CD28 Antigens ; CTLA-4 Antigen ; CTLA4 protein, human
Language	English
Publishing date	2013-11-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1300470
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Article ; Online: An LFA-1 (alphaLbeta2) small-molecule antagonist reduces inflammation and joint destruction in murine models of arthritis.

Suchard, Suzanne J / Stetsko, Dawn K / Davis, Patricia M / Skala, Stacey / Potin, Dominique / Launay, Michele / Dhar, T G Murali / Barrish, Joel C / Susulic, Vojkan / Shuster, David J / McIntyre, Kim W / McKinnon, Murray / Salter-Cid, Luisa

Journal of immunology (Baltimore, Md. : 1950)

2010 Volume 184, Issue 7, Page(s) 3917–3926

Abstract: LFA-1 appears to play a central role in normal immune responses to foreign Ags. In autoimmune or inflammatory diseases, there is increased expression of LFA-1 and/or its counterligand, ICAM-1. Others have demonstrated that the targeted disruption of LFA- ... ...

Abstract	LFA-1 appears to play a central role in normal immune responses to foreign Ags. In autoimmune or inflammatory diseases, there is increased expression of LFA-1 and/or its counterligand, ICAM-1. Others have demonstrated that the targeted disruption of LFA-1:ICAM interactions, either by gene deletion or Ab treatment in mice, results in reduced leukocyte trafficking, inflammatory responses, and inhibition of inflammatory arthritis in the K/BxN serum transfer model. However, there has been little success in finding a small-molecule LFA-1 antagonist that can similarly impact rodent models of arthritis. In this paper, we present the first reported example of an LFA-1 small-molecule antagonist, BMS-587101, that is efficacious in preclinical disease models. In vitro, BMS-587101 inhibited LFA-1-mediated adhesion of T cells to endothelial cells, T cell proliferation, and Th1 cytokine production. Because BMS-587101 exhibits in vitro potency, cross-reactivity, and oral bioavailability in rodents, we evaluated the impact of oral administration of this compound in two different models of arthritis: Ab-induced arthritis and collagen-induced arthritis. Significant impact of BMS-587101 on clinical score in both models was observed, with inhibition comparable or better than anti-mouse LFA-1 Ab. In addition, BMS-587101 significantly reduced cytokine mRNA levels in the joints of Ab-induced arthritis animals as compared with those receiving vehicle alone. In paws taken from the collagen-induced arthritis study, the bones of vehicle-treated mice had extensive inflammation and bone destruction, whereas treatment with BMS-587101 resulted in marked protection. These findings support the potential use of an LFA-1 small-molecule antagonist in rheumatoid arthritis, with the capacity for disease modification.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/pharmacology ; Arthritis, Experimental/drug therapy ; Arthritis, Experimental/immunology ; Arthritis, Experimental/pathology ; Cell Adhesion/drug effects ; Cell Proliferation/drug effects ; Cytokines/biosynthesis ; Cytokines/drug effects ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; Humans ; Inflammation/drug therapy ; Inflammation/immunology ; Inflammation/pathology ; Lymphocyte Culture Test, Mixed ; Lymphocyte Function-Associated Antigen-1/immunology ; Lymphocyte Function-Associated Antigen-1/metabolism ; Mice ; Spiro Compounds/pharmacology ; Thiophenes/pharmacology
Chemical Substances	5-(9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro(4,4)non-7-ylmethyl)-3-thiophenecarboxylic acid ; Anti-Inflammatory Agents ; Cytokines ; Lymphocyte Function-Associated Antigen-1 ; Spiro Compounds ; Thiophenes
Language	English
Publishing date	2010-04-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.0901095
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Article: Design of LFA-1 antagonists based on a 2,3-dihydro-1H-pyrrolizin-5(7aH)-one scaffold.

Dodd, Dharmpal S / Sheriff, Steven / Chang, ChiehYing J / Stetsko, Dawn K / Phillips, Linda M / Zhang, Yingru / Launay, Michele / Potin, Dominique / Vaccaro, Wayne / Poss, Michael A / McKinnon, Murray / Barrish, Joel C / Suchard, Suzanne J / Murali Dhar, T G

Bioorganic & medicinal chemistry letters

2007 Volume 17, Issue 7, Page(s) 1908–1911

Abstract: A new class of lymphocyte function-associated antigen-1 (LFA-1) antagonists is described. Elaboration of the 2,3-dihydro-1H-pyrrolizin-5(7aH)-one scaffold resulted in the synthesis of potent inhibitors of the LFA-1/ICAM-1 interaction. Along with the in ... ...

Abstract	A new class of lymphocyte function-associated antigen-1 (LFA-1) antagonists is described. Elaboration of the 2,3-dihydro-1H-pyrrolizin-5(7aH)-one scaffold resulted in the synthesis of potent inhibitors of the LFA-1/ICAM-1 interaction. Along with the in vitro activity, we present the X-ray crystal structure of the complex of compound 9b, in a novel binding mode to the I-domain of LFA-1.
MeSH term(s)	Chemistry, Pharmaceutical/methods ; Crystallography, X-Ray ; Drug Design ; Drug Screening Assays, Antitumor ; HeLa Cells ; Humans ; Inhibitory Concentration 50 ; Lymphocyte Function-Associated Antigen-1/chemistry ; Models, Chemical ; Molecular Conformation ; Pyrroles/chemistry ; Stereoisomerism ; Temperature ; X-Rays
Chemical Substances	Lymphocyte Function-Associated Antigen-1 ; Pyrroles
Language	English
Publishing date	2007-04-01
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2007.01.036
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Article ; Online: Small molecule antagonist of leukocyte function associated antigen-1 (LFA-1): structure-activity relationships leading to the identification of 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)nicotinic acid (BMS-688521).

Watterson, Scott H / Xiao, Zili / Dodd, Dharmpal S / Tortolani, David R / Vaccaro, Wayne / Potin, Dominique / Launay, Michele / Stetsko, Dawn K / Skala, Stacey / Davis, Patric M / Lee, Deborah / Yang, Xiaoxia / McIntyre, Kim W / Balimane, Praveen / Patel, Karishma / Yang, Zheng / Marathe, Punit / Kadiyala, Pathanjali / Tebben, Andrew J /

Sheriff, Steven / Chang, Chiehying Y / Ziemba, Theresa / Zhang, Huiping / Chen, Bang-Chi / DelMonte, Albert J / Aranibar, Nelly / McKinnon, Murray / Barrish, Joel C / Suchard, Suzanne J / Murali Dhar, T G

Journal of medicinal chemistry

2010 Volume 53, Issue 9, Page(s) 3814–3830

Abstract: Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or alpha(L)beta(2), belongs to the beta(2) integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion ... ...

Abstract	Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or alpha(L)beta(2), belongs to the beta(2) integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion molecules 1, 2, and 3 (ICAM 1, 2, and 3). The interactions between LFA-1 and the ICAMs are critical for cell adhesion, and preclinical animal studies and clinical data from the humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept for LFA-1 as an immunological target. This article will detail the structure-activity relationships (SAR) leading to a novel second generation series of highly potent spirocyclic hydantoin antagonists of LFA-1. With significantly enhanced in vitro and ex vivo potency relative to our first clinical compound (1), as well as demonstrated in vivo activity and an acceptable pharmacokinetic and safety profile, 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro-[4.4]nonan-7-yl)nicotinic acid (2e) was selected to advance into clinical trials.
MeSH term(s)	Humans ; Hydantoins/pharmacokinetics ; Hydantoins/pharmacology ; Immunologic Factors/chemistry ; Lymphocyte Function-Associated Antigen-1/chemistry ; Lymphocyte Function-Associated Antigen-1/drug effects ; Lymphocyte Function-Associated Antigen-1/immunology ; Nicotinic Acids/pharmacokinetics ; Nicotinic Acids/toxicity ; Structure-Activity Relationship
Chemical Substances	Hydantoins ; Immunologic Factors ; Lymphocyte Function-Associated Antigen-1 ; Nicotinic Acids
Language	English
Publishing date	2010-05-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/jm100348u
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Article: De novo design, synthesis, and in vitro activity of LFA-1 antagonists based on a bicyclic[5.5]hydantoin scaffold.

Potin, Dominique / Launay, Michele / Nicolai, Eric / Fabreguette, Maud / Malabre, Patrice / Caussade, François / Besse, Dominique / Skala, Stacey / Stetsko, Dawn K / Todderud, Gordon / Beno, Brett R / Cheney, Daniel L / Chang, Chiehying J / Sheriff, Steven / Hollenbaugh, Diane L / Barrish, Joel C / Iwanowicz, Edwin J / Suchard, Suzanne J / Dhar, T G Murali

Bioorganic & medicinal chemistry letters

2005 Volume 15, Issue 4, Page(s) 1161–1164

Abstract: LFA-1 (leukocyte function-associated antigen-1), is a member of the beta(2)-integrin family and is expressed on all leukocytes. The LFA-1/ICAM interaction promotes tight adhesion between activated leukocytes and the endothelium, as well as between T ... ...

Abstract	LFA-1 (leukocyte function-associated antigen-1), is a member of the beta(2)-integrin family and is expressed on all leukocytes. The LFA-1/ICAM interaction promotes tight adhesion between activated leukocytes and the endothelium, as well as between T cells and antigen-presenting cells. Evidence from both animal models and clinical trials provides support for LFA-1 as a target in several different inflammatory diseases. This paper describes the de novo design, synthesis and in vitro activity of LFA-1 antagonists based on a bicyclic[5.5]hydantoin scaffold.
MeSH term(s)	Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Drug Design ; HeLa Cells ; Humans ; Hydantoins/chemical synthesis ; Hydantoins/pharmacology ; Inflammation/drug therapy ; Inhibitory Concentration 50 ; Intercellular Adhesion Molecule-1/chemistry ; Lymphocyte Function-Associated Antigen-1/chemistry ; Lymphocyte Function-Associated Antigen-1/drug effects ; Molecular Conformation ; Protein Binding/drug effects ; Structure-Activity Relationship
Chemical Substances	Bridged Bicyclo Compounds, Heterocyclic ; Hydantoins ; Lymphocyte Function-Associated Antigen-1 ; Intercellular Adhesion Molecule-1 (126547-89-5)
Language	English
Publishing date	2005-02-15
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2004.12.007
Database	MEDical Literature Analysis and Retrieval System OnLINE

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