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Anti-arthritic effects of the novel dipeptidyl peptidase IV inhibitors TMC-2A and TSL-225
We evaluated the immunopharmacological effects of two novel dipeptidyl peptidase IV (DP IV) 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...
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Published in: | Immunopharmacology 1998-07, Vol.40 (1), p.21-26 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | We evaluated the immunopharmacological effects of two novel dipeptidyl peptidase IV (DP IV) 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 Ki value of 5.3 μM. 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 Ki value of 3.6 μM. 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. |
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ISSN: | 0162-3109 |
DOI: | 10.1016/S0162-3109(98)00014-9 |