Synthesis of monomeric and polymeric conjugates carrying a thrombin inhibitor through an ester bond.
Four kinds of monomers carrying a thrombin inhibitor, (2R,4R)-4-methyl-1-[N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfon yl]-L-arginyl]-2-piperidinecarboxylic acid (argatroban), were synthesized. These monomers were copolymerized with acrylamide to yield water-soluble polymeric conjugates possessing the argatroban moiety in the side chain. Their antithrombogenic activities were determined from the inhibitory effect on thrombin action and the prolongation effect on blood clotting time. The monomeric conjugates of 2-hydroxyethyl acrylate (HEA), 2-hydroxyethyl methacrylate (HEMA), and 4-hydroxybutyl acrylate (HBA) linked with argatroban through an ester bond were potent inhibitors of thrombin, prolonging the blood-clotting time, whereas a conjugate of amino methyl styrene (AMS) and argatroban through an amide bond was a less potent inhibitor than argatroban. None of the copolymers could prolong blood clotting when assessed just after preparation of their aqueous solutions, but the antithrombogenic activity of the aqueous solutions increased after incubation for 7 days at 37 degrees C for the polymeric conjugates through an ester bond. Free argatroban was detected in the aqueous solutions of polymeric conjugates after incubation, suggesting that argatroban was released by hydrolysis of the ester bond during incubation.
Noguchi
H
H
Research Center for Biomedical Engineering, Kyoto University, Japan.
Iwata
H
H
Ikada
Y
Y
D000991:Antithrombins / Q000138:chemical synthesis* / Q000737:chemistry; D001120:Arginine / Q000031:analogs & derivatives; D001777:Blood Coagulation / Q000187:drug effects; D004952:Esters; D006801:Humans; D010875:Pipecolic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011108:Polymers; D013449:Sulfonamides
D000991:Antithrombins; D004952:Esters; D010875:Pipecolic Acids; D011108:Polymers; D013449:Sulfonamides; D001120:Arginine; C031942:argatroban