Synthesis and optimization of hyaluronic acid-methotrexate conjugates to maximize benefit in the treatment of osteoarthritis.
We previously reported that a conjugate of hyaluronic acid (HA) and methotrexate (MTX) could be a prototype for future osteoarthritis drugs having the efficacy of the two clinically validated agents but with a reduced risk of the systemic side effects of MTX by using HA as the drug delivery carrier. To identify a clinical candidate, we attempted optimization of a lead, conjugate 1. Initially, in fragmentation experiments with cathepsins, we optimized the peptide part of HA-MTX conjugates to be simpler and more susceptible to enzymatic cleavage. Then we optimized the peptide, the linker, the molecular weight, and the binding ratio of the MTX of the conjugates to inhibit proliferation of human fibroblast-like synoviocytes in vitro and knee swelling in rat antigen-induced monoarthritis in vivo. Consequently, we found conjugate 30 (DK226) to be a candidate drug for the treatment of osteoarthritis.
Homma
Akie
A
Research Division, Chugai Pharmaceutical Co, Ltd, 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
Sato
Haruhiko
H
Tamura
Tatsuya
T
Okamachi
Akira
A
Emura
Takashi
T
Ishizawa
Takenori
T
Kato
Tatsuya
T
Matsuura
Tetsu
T
Sato
Shigeo
S
Higuchi
Yoshinobu
Y
Watanabe
Tomoyuki
T
Kitamura
Hidetomo
H
Asanuma
Kentaro
K
Yamazaki
Tadao
T
Ikemi
Masahisa
M
Kitagawa
Hironoshin
H
Morikawa
Tadashi
T
Ikeya
Hitoshi
H
Maeda
Kazuaki
K
Takahashi
Koichi
K
Nohmi
Kenji
K
Izutani
Noriyuki
N
Kanda
Makoto
M
Suzuki
Ryohchi
R
D000818:Animals; D002403:Cathepsins / Q000378:metabolism; D002460:Cell Line; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D006820:Hyaluronic Acid / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D007719:Knee Joint / Q000187:drug effects / Q000473:pathology; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D010003:Osteoarthritis / Q000188:drug therapy*; D051381:Rats; D011917:Rats, Inbred Lew; D013582:Synovial Fluid / Q000166:cytology
C000611759:DK226 compound; D006820:Hyaluronic Acid; D002403:Cathepsins; D008727:Methotrexate