title: Towards dual antithrombotic compounds - balancing thrombin inhibitory and fibrinogen GPIIb/IIIa binding inhibitory activities of 2,3-dihydro-1,4-benzodioxine derivatives through regio- and stereoisomerism.
abstract: Enantiomers of 2,3-dihydro-1,4-benzodioxine derivatives possessing both thrombin and fibrinogen GPIIb/IIIa binding inhibitory activities were prepared from (R)- and (S)-glycidol as potential dual antithrombotic compounds. The influence of chirality and substitution pattern on thrombin inhibition and on inhibition of fibrinogen binding to GPIIb/IIIa was analyzed. Docking studies were used in an attempt to rationalize the results. The (S)-isomers of both 2,3-dihydro-1,4-benzodioxine regioisomers at positions 6 and 7 were found to be better thrombin inhibitors than the corresponding (R)-enantiomers, whereas we observed that stereochemistry does not display a consistent influence on fibrinogen GPIIb/IIIa binding inhibitory activity. Compound 11b, the (S)-isomer of the 6-substituted regioisomer, possessed the best balanced dual activity, with Ki(thrombin) = 1.67 ± 0.27 μM and IC50(GPIIb/IIIa) = 0.665 ± 0.26 μM, raising the hope that merging anticoagulant and platelet antiaggregatory activities in the same molecule could lead to successful multitarget antithrombotic agents.
authors: University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors: Miloš
authors: M
authors: Ilić
authors: Petra
authors: P
authors: Dunkel
authors: Janez
authors: J
authors: Ilaš
authors: Ewa
authors: E
authors: Chabielska
authors: Agnieszka
authors: A
authors: Zakrzeska
authors: Péter
authors: P
authors: Mátyus
authors: Danijel
authors: D
authors: Kikelj
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D004146:Dioxanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010070:Oxalates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: C583781:2-(benzyl(2-((4-carbamimidoylphenoxy)methyl)-2,3-dihydro-1,4-benzodioxin-6-yl)amino)-2-oxoacetic acid; D004146:Dioxanes; D005343:Fibrinolytic Agents; D010070:Oxalates; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013917:Thrombin