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

a b s t r a c tEnantiomers 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 K i(thrombin) ¼ 1.67 AE 0.27 mM and IC 50(GPIIb/ IIIa) ¼ 0.665 AE 0.26 mM, raising the hope that merging anticoagulant and platelet antiaggregatory activities in the same molecule could lead to successful multitarget antithrombotic agents.

Design, synthesis of novel tryptophan derivatives for antiplatelet aggregation activity based on tripeptide pENW (pGlu-Asn-Trp)

“…One of the major drawbacks of GPIIb/IIIa antagonists reported in many literatures [24,25] is the risk of bleeding. Thus, the bleeding time of 87 has been measured in a tail transection method in comparison with pENW and Tirofiban.…”

3,1-Benzothiazines, 1,4-Benzodioxines and 1,4-Benzoxazines as Inhibitors of Matriptase-2: Outcome of a Focused Screening Approach

“…Besides thrombin, activity against related serine proteases, e.g., trypsin and factor Xa, has also been identified. The enantiomers ( S )- 10 and ( R )- 10 as well as ( S )- 11 and ( R )- 11 , represent 6- and 7-substituted isomers [ 38 ].…”

“…Among the pairs of enantiomers, the ( S )-configuration was somewhat preferred for matriptase-2 inhibition (( S )- 10 versus ( R )- 10 and ( S )- 11 versus ( R )- 11 ). It should be noted that ( S )- 12 was described to be a highly potent thrombin inhibitor [ 38 ]. However, thrombin inhibition is not always accompanied by matriptase-2 inhibition.…”

Progress in the Research of GPIIb/IIIa Antagonists

“…One way of antiplatelet therapy is to block the stimulus including epinephrine, thrombin, collagen and ADP. Thrombin, for example, is a trypsin-like serine protease that cleaves fibrinogen to insoluble fibrin and amplifies its own production via activation of two cofactors, factor V and factor VIII in blood coagulation cascade [5]. Thrombin also promotes platelet aggregation by binding to a specific receptor on the platelet surface.…”

“…The RGD sequence contains the terminal carboxylic group, and several thrombin inhibitors, for example, melagatranand dabigatran, showed the good tolerability of the P3 carboxylic group. Some of these compounds, such as 71, 72 and 73 (71-75, Figure 15) possessed a well balancing activity at both targets, and they were good starting point for further optimization [67,68].…”