Bioorganic and Medicinal Chemistry p. 765 - 778 (1997)
Update date:2022-08-05
Topics: Chemical Synthesis In vitro Testing Clinical Trials Structural Optimization Formulation Development Regulatory Approval Drug Design Pharmacokinetics (PK) Studies Toxicology Studies In Vivo Efficacy
Hirayama, Ryoichi
Yamamoto, Minoru
Tsukida, Takahiro
Matsuo, Konomi
Obata, Yuji
Sakamoto, Fumio
Ikedaa, Shoji
The synthesis and biological evaluation of orally active inhibitors of matrix metalloproteinase are reported. Modifications of the P2' position and the α-substituent of hydroxamic acid derivatives were carried out, and revealed that the P2' substituent influenced the MMP inhibitory activities in vitro and in plasma after oral administration. The hydroxamates with phenylglycine at the P2' position were absorbed well orally. Compound 15e, which exhibited the longest duration of inhibitory activity in plasma after oral administration among the phenylglycine derivatives (5a-5d, 15a, 15c, 15e), was evaluated in a rat adjuvant arthritis model. A reduction in hind foot pad swelling and improvements of some inflammatory parameters were demonstrated when the compound was administered orally. These results indicate the potential of MMP inhibitors for rheumatoid arthritis.
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