Design and synthesis of an orally active GPIIb/IIIa antagonist based on a phenylpiperazine scaffold

J H van Maarseveen; J A den Hartog; K Tipker; J H Reinders; J Brakkee; U Schön; W Kehrbach; C G Kruse

doi:10.1016/s0960-894x(98)00257-1

Design and synthesis of an orally active GPIIb/IIIa antagonist based on a phenylpiperazine scaffold

Bioorg Med Chem Lett. 1998 Jun 16;8(12):1531-6. doi: 10.1016/s0960-894x(98)00257-1.

Authors

J H van Maarseveen¹, J A den Hartog, K Tipker, J H Reinders, J Brakkee, U Schön, W Kehrbach, C G Kruse

Affiliation

¹ Solvay Pharmaceuticals Research Laboratory, Weesp, The Netherlands. jan.vanmaarseveen@solvay.com

PMID: 9873384
DOI: 10.1016/s0960-894x(98)00257-1

Abstract

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.

MeSH terms

Animals
Cricetinae
Drug Design*
Fibrinolytic Agents / chemical synthesis*
Fibrinolytic Agents / chemistry
Fibrinolytic Agents / pharmacology
Guinea Pigs
Humans
Magnetic Resonance Spectroscopy
Mass Spectrometry
Piperazines / chemistry*
Platelet Aggregation Inhibitors / chemical synthesis*
Platelet Aggregation Inhibitors / chemistry
Platelet Aggregation Inhibitors / pharmacology
Platelet Glycoprotein GPIIb-IIIa Complex / antagonists & inhibitors*
Thrombosis / prevention & control

Substances

Fibrinolytic Agents
Piperazines
Platelet Aggregation Inhibitors
Platelet Glycoprotein GPIIb-IIIa Complex
phenylpiperazine