ANTIARTHRITIC EFFECTS OF THE NOVEL DIPEPTIDYL PEPTIDASE-IV INHIBITORSTMC-2A AND TSL-225

We evaluated the immunopharmacological effects of two novel dipeptidyl peptidase I (DP I) inhibitors, TMC-2A 3'''-yl)-1''-oxopropyl]-1',2',3 ',4'-tetrahydro-6', -carbonylamino]-4-hydroxymethyl-5-hydroxypentanoic acid] and TSL-225 tophyl-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 s uppressed alkyldiamine yl-N',N-bis(2-hydroxyethyl)propanediamine)-indu ced arthritis. We developed a chemically modified inhibitor, TSL-225, with potency similar to that of TMC-2A. TSL-225 inhibited DP IV uncomp etitively, with a K-i value of 3.6 mu M. TSL-225 was also effective ag ainst adjuvant-induced arthritis. These results suggest that TMC-2A an d 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.