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

• Published in: Chemical & Pharmaceutical Bulletin Vol. 52; no. 6; pp. 675 - 687
• Main Authors: Kaneko, Toshihiko, Clark, Richard S. J., Ohi, Norihito, Ozaki, Fumihiro, Kawahara, Tetsuya, Kamada, Atsushi, Okano, Kazuo, Yokohama, Hiromitsu, Ohkuro, Masayoshi, Muramoto, Kenzo, Takenaka, Osamu, Kobayashi, Seiichi
• Format: Journal Article
• Language: English; Japanese
• Published: TOKYO The Pharmaceutical Society of Japan 01.06.2004; Pharmaceutical Society of Japan; Pharmaceutical Soc Japan; Japan Science and Technology Agency
• Subjects: 10H-pyrazino[2,3-b][1,4]benzothiazine; adhesion molecule inhibitor; Administration, Oral; Animals; Benzothiadiazines - administration & dosage; Benzothiadiazines - chemistry; Carboxylic Acids - administration & dosage; Carboxylic Acids - chemistry; Cell Adhesion Molecules - antagonists & inhibitors; Cell Adhesion Molecules - physiology; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; ER-49890; Female; Intercellular Adhesion Molecule-1 - physiology; Life Sciences & Biomedicine; Male; Pharmacology & Pharmacy; Physical Sciences; Piperidines - administration & dosage; Piperidines - chemistry; Rats; Rats, Inbred F344; Rats, Inbred Lew; Science & Technology; Thiazines - administration & dosage; Thiazines - chemistry; CELLS; ACTIVATION; adhesion molecule inhibitor; ICAM-1; ER-49890; 10H-pyrazino[2,3-b][1,4]benzothiazine; EXPRESSION
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.52.675

Novel piperidine carboxylic acid derivatives of 10H-pyrazino[2,3-b][1,4]benzothiazine were prepared and evaluated for their inhibitory activity on the upregulation of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1). Replacement of the methanesulfonyl group on the piperidine ring of previously prepared derivatives with a carboxylic acid-containing moiety resulted in a number of potent adhesion molecule inhibitors. Of these, (anti) [3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methyl-3-azabicyclo[3.3.1]non-9-yl]acetic acid 2q (ER-49890), showed the most potent oral inhibitory activities against neutrophil migration in an interleukin-1 (IL-1) induced paw inflammation model using mice, and leukocyte accumulation in a carrageenan pleurisy model in the rat, and therapeutic effect on collagen-induced arthritis in rats.