143217-95-2Relevant academic research and scientific papers
Synthesis and biological activity of ketomethylene pseudopeptide analogues as thrombin inhibitors
Cheng,Goodwin,Schully,Kakkar,Claeson
, p. 3364 - 3369 (2007/10/02)
Ketomethylene pseudopeptide analogues Aa-Pro-Argψ(COCH2)Gly-pip, 1, where Aa are D- or L-amino acids (Dpa, β,β-diphenylalanine; αNal, α- naphthylalanine; βNal, β-naphthylalanine; Fgl, fluorenylglycine) with highly lipophilic side chains and ψ(COCH2) is a ketomethylene pseudopeptide bond, have been synthesized through a modified Dakin-West reaction under very mild conditions with a high yield using tripeptide 4 with a labile functional group directly on the side chain. Their enzymatic assay of thrombin inhibition has been carried out. The structure-activity relationship study indicated that a lipophilic side chain on the amino acid in the P3 position is very important for binding to the apolar site of thrombin. Compound 1a with D-Dpa at the P3 position has a K(i) of 0.2 μM and it doubles thrombin clotting time at only 3 times higher concentration. These values are about 7 times better than those of the corresponding D-Phe analogues. Furthermore, 1a shows poor inhibitory activity against plasmin, factor Xa, urokinase, and kallikrein. Preliminary in vivo testing (3-4-kg rabbit as the animal model) shows no observable side effect (change of blood pressure and accumulation of blood platelet in lungs) at a dose of 1 mg/kg.
