Design, synthesis and biological activity of novel rigid amidino-phenylalanine derivatives as inhibitors of thrombin.
(3S)-(Naphthalene-2-sulfonylamino)-1-[2R-(4-amidinophenyl)-1- piperidinocarbonylethyl]-2-pyrrolidinone (1a) is a potent inhibitor of thrombin with an IC50 value by 112 times lower than that of NAPAP (racemate). The selectivity versus trypsin can be improved by incorporation of substituents on the naphthyl ring. The mode of binding of the compound was determined by X-ray crystallography.
Mack
H
H
Main Laboratory, Pharmaceuticals Research, Ludwigshafen, Germany.
Pfeiffer
T
T
Hornberger
W
W
Böhm
H J
HJ
Höffken
H W
HW
D000818:Animals; D000991:Antithrombins / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001550:Benzamidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D006860:Hydrogen Bonding; D007769:Lactams / Q000138:chemical synthesis / Q000494:pharmacology; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism
C097937:3-(naphthalene-2-sulfonylamino)-1-(2-(4-amidinophenyl)-1-piperidinocarbonylethyl)-2-pyrrolidinone; D000991:Antithrombins; D001550:Benzamidines; D004151:Dipeptides; D007769:Lactams; D010880:Piperidines; D011760:Pyrrolidinones; D015842:Serine Proteinase Inhibitors; C038708:N(alpha)-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide; D014357:Trypsin; D013917:Thrombin