Piperidine carboxylic acid derivatives of 10H-pyrazino[2,3-b][1,4]benzothiazine as orally-active adhesion molecule inhibitors.
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.
Kaneko
Toshihiko
T
Tsukuba Research Laboratories, Eisai Co. Ltd., 5-1-3 Tokudai, Tsukuba, Ibaraki 300-2635, Japan. t3-kaneko@hhc.eisai.co.jp
Clark
Richard S J
RS
Ohi
Norihito
N
Ozaki
Fumihiro
F
Kawahara
Tetsuya
T
Kamada
Atsushi
A
Okano
Kazuo
K
Yokohama
Hiromitsu
H
Ohkuro
Masayoshi
M
Muramoto
Kenzo
K
Takenaka
Osamu
O
Kobayashi
Seiichi
S
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*
D001581:Benzothiadiazines; D002264:Carboxylic Acids; D015815:Cell Adhesion Molecules; D010880:Piperidines; D013843:Thiazines; D018799:Intercellular Adhesion Molecule-1