Anti-arthritic effects of the novel dipeptidyl peptidase IV inhibitors TMC-2A and TSL-225

被引：41

作者：

Tanaka, S ^{[1
]}

Murakami, T ^{[1
]}

Nonaka, N ^{[1
]}

Ohnuki, T ^{[1
]}

Yamada, M ^{[1
]}

Sugita, T ^{[1
]}

机构：

[1] Tanabe Seiyaku Co Ltd, Discovery Res Lab, Yodogawa Ku, Osaka 5328505, Japan

来源：

IMMUNOPHARMACOLOGY | 1998年 / 40卷 / 01期

关键词：

dipeptidyl peptidase IV; CD26; protease inhibitor; arthritis; TMC-2A; TSL-225;

D O I：

10.1016/S0162-3109(98)00014-9

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

We evaluated the immunopharmacological effects of two novel dipeptidyl peptidase I (DP I) inhibitors, TMC-2A [(2S,2S',2S")-2-[2'-[2"-amino-3''-(-indol-3'''-yl)-1"-oxopropyl]-1',2',3',4'-tetrahydro-6', 8'-dihydroxy-7'-methoxyisoquinol-3-yl-carbonylamino]-4-hydroxymethyl-5-hydroxypentanoic acid] and TSL-225 (tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid). TMC-2A, produced by Aspergillus sp. A374, inhibited rat kidney DP IV uncompetitively, with a K-i value of 5.3 mu M. In vivo, TMC-2A suppressed alkyldiamine (N,N-dioctadecyl-N',N-bis(2-hydroxyethyl)propanediamine)-induced arthritis. We developed a chemically modified inhibitor, TSL-225, with potency similar to that of TMC-2A. TSL-225 inhibited DP IV uncompetitively, with a K-i value of 3.6 mu M. TSL-225 was also effective against adjuvant-induced arthritis. These results suggest that TMC-2A and its derivatives may have therapeutic potential for the treatment of inflammatory diseases such as rheumatoid arthritis. (C) 1998 Elsevier Science B.V. All rights reserved.

引用

页码：21 / 26

页数：6

共 16 条

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