Inhibitors of Adhesion Molecules Expression; The Synthesis and Pharmacological Properties of 10H-Pyrazino[2,3-b][1,4]benzothiazine Derivatives.

Kaneko, Toshihiko; Clark, Richard S. J.; Ohi, Norihito; Kawahara, Tetsuya; Akamatsu, Hiroshi; Ozaki, Fumihiro; Kamada, Atsushi; Okano, Kōji; Yokohama, Hiromitsu; Muramoto, Koji; Ohkuro, Masayoshi; Takenaka, Osamu; Kobayashi, Seiichi

doi:10.1248/cpb.50.922

Cited by 22 publications

(16 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our previous report, 12) the preferable ClogP value of sulfonamide derivatives, 1a and 1b that were highly potent in the IL-1 paw inflammation model, were stated to be around 0.6 as calculated using a previous version of ClogP software. We have also calculated and compared the values for carboxylic acid derivatives.…”

Section: Resultsmentioning

confidence: 98%

“…With the exceptions of 2j, 2k and 2l, piperidine carboxylic acid derivatives of 10H-pyrazino [2,3- 12) with the appropriate piperidine carboxylates 4a-i and 4m-v in DMF using K 2 CO 3 provided the esters 5a-i and 5m-v. Hydrolysis of these esters under alkaline conditions provided the desired compounds 2a-i and 2m-v.…”

Section: Piperidine Carboxylic Acid Derivatives Of 10h-pyrazino[23-bmentioning

confidence: 99%

“…Protection of readily available ester 46 12) with methoxymethyl chloride (MOMCl) gave the compound 47, which was reduced with lithium aluminum hydride (LiAlH 4 ) and chlorinated to afford the intermediate 49. Cyanation of 49 followed by hydrolysis and esterification gave 51.…”

Section: Piperidine Carboxylic Acid Derivatives Of 10h-pyrazino[23-bmentioning

confidence: 99%

“…[8][9][10][11] We have reported that the piperidine sulfonamide and sulfamide derivatives of 10H-pyrazino [2,3-b] [1,4]benzothiazine 1a and 1b have potent ICAM-1 upregulation inhibitory activity and suppresses neutrophil infiltration in an IL-1-induced paw inflammation model. 12) We report here the effect of replacing the piperidine sulfonamide moiety of 1a in order to investigate further the structure-activity relationships of this family. Of particular interest to us was the introduction of a carboxylic acid group, a bioisostere of the sulfonamide function.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Piperidine Carboxylic Acid Derivatives of 10H-Pyrazino[2,3-b][1,4]benzothiazine as Orally-Active Adhesion Molecule Inhibitors

et al. 2004

Self Cite

View full text Add to dashboard Cite

Adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1), E-selectin and vascular cell adhesion molecule-1 (VCAM-1), play a pivotal role in the inflammatory and immunological responses. They are initially upregulated on the endothelium by tumor necrosis factor-a (TNF-a) or interleukin-1 (IL-1) and go on to mediate the steps of leukocyte migration from the vasculature into the inflamed tissue, these leukocytes then promote the inflammatory response. 1)Also, the interaction of ICAM-1 and VCAM-1 expressed on antigen presenting cells with their ligands, such as lymphocyte function associated antigen-1 (LFA-1) and very late activation antigen-4 (VLA-4), has been involved in activation of T cells. [2][3][4][5] Recently, the antigen recognition step has been visualized and ICAM-1 identified as one important component of the immunological synapse. 6) Hence, it is hoped that interfering with these interactions will not only have an effect on leukocyte infiltration, but also modulate T cell response. Furthermore, it has been reported that anti-adhesion molecule antibodies can ameliorate the inflammatory reaction and immunological parameters in various animal models. 7) For these reasons the development of cell adhesion molecule inhibitors as novel therapeutics for inflammatory and autoimmune diseases has been widely anticipated, and a considerable literature on such compounds has appeared. [8][9][10][11] We have reported that the piperidine sulfonamide and sulfamide derivatives of 10H-pyrazino [2,3-b][1,4]benzothiazine 1a and 1b have potent ICAM-1 upregulation inhibitory activity and suppresses neutrophil infiltration in an IL-1-induced paw inflammation model. 12) We report here the effect of replacing the piperidine sulfonamide moiety of 1a in order to investigate further the structure-activity relationships of this family. Of particular interest to us was the introduction of a carboxylic acid group, a bioisostere of the sulfonamide function.Chemistry We first prepared the right moieties of the compounds 2. The piperidine carboxylates 4a-c are either commercially available or known in the literature. 13,14) The other piperidine carboxylates 4d-i and 4l-v were prepared as shown in Charts 1-11. The syntheses of 4d and 4e are shown in Chart 1. Coupling the aldehyde 6 15) with the appropriate Horner-Emmons reagent gave the unsaturated ester 7. Hydrogenation of the resulting ester 7 using 10% palladium on carbon (Pd/C) followed by deprotection of the piperidine amine group with 4 N HCl/AcOEt provided saturated ester 4d. The unsaturated ester 4e was also obtained by removal of the Boc group of compound 7 using the same procedure.The acetylenic ester 4f was prepared as shown in Chart 2. Reaction of 4-piperidine aldehyde 9 with the Corey-Fuchs ; 5-1-3, Tokodai, Tsukuba, Ibaraki 300-2635, Japan: and b Eisai Research Institute of Boston, Inc.; 4 Corporate Drive, Andover, Massachusetts, 01810-2441, U.S.A. Received December 18, 2003 accepted March 3, 2004 Novel piperidine

show abstract

Section: Resultsmentioning

confidence: 98%

Section: Piperidine Carboxylic Acid Derivatives Of 10h-pyrazino[23-bmentioning

confidence: 99%

Section: Piperidine Carboxylic Acid Derivatives Of 10h-pyrazino[23-bmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Piperidine Carboxylic Acid Derivatives of 10H-Pyrazino[2,3-b][1,4]benzothiazine as Orally-Active Adhesion Molecule Inhibitors

et al. 2004

Self Cite

View full text Add to dashboard Cite

show abstract

“…The quantification of adhesion molecule expression was determined by the enzyme-linked immunosorbent assay as previously reported (26).…”

Section: Quantification Of Adhesion Molecule Expression On Huvecmentioning

confidence: 99%

The α integrin cytoplasmic motif KXGFFKR is essential for integrin-mediated leukocyte adhesion

Ohkuro

Hishinuma²

2010

Int J Mol Med

View full text Add to dashboard Cite

Abstract. During the development of autoimmune and inflammatory diseases, infiltration by multiple leukocyte types is commonly observed at the site of inflammation. These cells are chemotactically recruited via activated integrins expressed on their cell surfaces. However, the detailed mechanism of integrin activation has not been fully elucidated. A specific and highly conserved cytoplasmic amino acid sequence, lysine-x-glycine-phenylalanine-phenylalanine-lysine-arginine (KXGFFKR), is located in the immediate vicinity of the membrane-spanning domain of all · integrins. In this study, we investigated the role of the KXGFFKR motif in the adhesion of leukocytes to human umbilical-vein endothelial cells (HUVEC). Pre-treatment of human neutrophils with a membrane-permeable peptide-linked KVGFFKR decreased cell adhesion to HUVEC induced by a complement activation product, C5a and formyl-methionine-leucine-phenylalanine. Similar inhibitory efficacies of this peptide were observed in T cell adhesion. Our data therefore demonstrate that a highly conserved sequence in the · integrins, KXGFFKR, is pharmacologically essential for integrin activation during leukocyte adhesion by both neutrophils and T cells.

show abstract

Inhibitors of Adhesion Molecules Expression; The Synthesis and Phamacological Properties of 10H‐Pyrazino[2,3‐b][1,4]benzothiazine Derivatives.

Kaneko

2002

ChemInform

View full text Add to dashboard Cite

show abstract

Inhibitors of Adhesion Molecules Expression; The Synthesis and Pharmacological Properties of 10H-Pyrazino[2,3-b][1,4]benzothiazine Derivatives.

Cited by 22 publications

References 53 publications

Piperidine Carboxylic Acid Derivatives of 10H-Pyrazino[2,3-b][1,4]benzothiazine as Orally-Active Adhesion Molecule Inhibitors

Piperidine Carboxylic Acid Derivatives of 10H-Pyrazino[2,3-b][1,4]benzothiazine as Orally-Active Adhesion Molecule Inhibitors

The α integrin cytoplasmic motif KXGFFKR is essential for integrin-mediated leukocyte adhesion

Inhibitors of Adhesion Molecules Expression; The Synthesis and Phamacological Properties of 10H‐Pyrazino[2,3‐b][1,4]benzothiazine Derivatives.

Contact Info

Product

Resources

About