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-car bonylamino]-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 microM. 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 microM. 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.
Discovery Research Laboratory, Osaka, Japan.
S
S
Tanaka
T
T
Murakami
N
N
Nonaka
T
T
Ohnuki
M
M
Yamada
T
T
Sugita
D000276:Adjuvants, Immunologic; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology; D001230:Aspergillus / Q000187:drug effects / Q000201:enzymology; D003959:Diamines; D018819:Dipeptidyl Peptidase 4 / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007211:Indoles / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D011916:Rats, Inbred F344; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D044005:Tetrahydroisoquinolines
D000276:Adjuvants, Immunologic; D003959:Diamines; D007211:Indoles; D007546:Isoquinolines; D015842:Serine Proteinase Inhibitors; C108548:TMC 2A; C115967:TSL 225; D044005:Tetrahydroisoquinolines; D018819:Dipeptidyl Peptidase 4; C006270:avridine