title: Piperidine carboxylic acid derivatives of 10H-pyrazino[2,3-b][1,4]benzothiazine as orally-active adhesion molecule inhibitors.
abstract: 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.
authors.affiliation: Tsukuba Research Laboratories, Eisai Co. Ltd., 5-1-3 Tokudai, Tsukuba, Ibaraki 300-2635, Japan. t3-kaneko@hhc.eisai.co.jp
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kaneko
authors.forename: Richard S J
authors.initials: RS
authors.lastname: Clark
authors.forename: Norihito
authors.initials: N
authors.lastname: Ohi
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Ozaki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kawahara
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kamada
authors.forename: Kazuo
authors.initials: K
authors.lastname: Okano
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Yokohama
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Ohkuro
authors.forename: Kenzo
authors.initials: K
authors.lastname: Muramoto
authors.forename: Osamu
authors.initials: O
authors.lastname: Takenaka
authors.forename: Seiichi
authors.initials: S
authors.lastname: Kobayashi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001581:Benzothiadiazines / Q000008:administration & dosage / Q000737:chemistry; D002264:Carboxylic Acids / Q000008:administration & dosage / Q000737:chemistry*; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000502:physiology; D005260:Female; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D013843:Thiazines / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: D001581:Benzothiadiazines; D002264:Carboxylic Acids; D015815:Cell Adhesion Molecules; D010880:Piperidines; D013843:Thiazines; D018799:Intercellular Adhesion Molecule-1