Design and synthesis of an orally active GPIIb/IIIa antagonist based on a phenylpiperazine scaffold.
The design and synthesis of an orally active LMW non-peptide GPIIb/IIIa antagonist, based on a N,N'-bisphenylpiperazine scaffold, is described. The optimal compound showed a high in vitro binding potency (pIC50 = 8.7) in combination with potent oral antithrombotic activity (30-40% inhibition of thrombus growth at 0.3-3 mg/kg) with a duration of action of > 90 min. in a hamster cheek pouch model.
van Maarseveen
J H
JH
Solvay Pharmaceuticals Research Laboratory, Weesp, The Netherlands. jan.vanmaarseveen@solvay.com
den Hartog
J A
JA
Tipker
K
K
Reinders
J H
JH
Brakkee
J
J
Schön
U
U
Kehrbach
W
W
Kruse
C G
CG
D000818:Animals; D006224:Cricetinae; D015195:Drug Design; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010879:Piperazines / Q000737:chemistry*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000517:prevention & control
D005343:Fibrinolytic Agents; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C031503:phenylpiperazine