- Synthesis and biological evaluation of direct thrombin inhibitors bearing 4-(piperidin-1-yl)pyridine at the P1 position with potent anticoagulant activity
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The design and synthesis of a new class of nonpeptide direct thrombin inhibitors, built on the structure of 1-(pyridin-4-yl)piperidine-4-carboxamide, are described. Starting from a strongly basic 1-amidinopiperidine derivative (6) showing poor thrombin (fIIa) and factor Xa (fXa) inhibition activities, anti-fIIa activity and artificial membrane permeability were considerably improved by optimizing the basic P1 and the X-substituted phenyl P4 binding moieties. Structure-activity relationship studies, usefully complemented with molecular modeling results, led us to identify compound 13b, which showed excellent fIIa inhibition (Ki = 6 nM), weak anti-Xa activity (K i = 5.64 μM), and remarkable selectivity over other serine proteases (e.g., trypsin). Compound 13b showed in vitro anticoagulant activity in the low micromolar range and significant membrane permeability. In mice (ex vivo), 13b demonstrated anticoagulant effects at 2 h after oral dosing (100 mg·kg-1), with a significant 43% prolongation of the activated partial thromboplastin time (aPTT), over controls (P 0.05).
- De Candia, Modesto,Fiorella, Filomena,Lopopolo, Gianfranco,Carotti, Andrea,Romano, Maria Rosaria,Lograno, Marcello Diego,Martel, Sophie,Carrupt, Pierre-Alain,Belviso, Benny D.,Caliandro, Rocco,Altomare, Cosimo
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p. 8696 - 8711
(2013/12/04)
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- FUSED FURAN COMPOUND
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The present invention provides a condensed furan compound of the formula (I): wherein Ring X is benzene, pyridine, or the like; Y is an optionally substituted amino, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted saturated heterocyclic group, an optionally substituted unsaturated heterocyclic group; A is a single bond, lower alkylene, lower alkenylidene, lower alkenylene or an oxygen atom; R3 is hydrogen or the like; and , R4 is hydrogen, or the like, or pharmaceutically acceptable salts thereof, which is useful as a medicament, particularly, as an activated blood coagulation factor X inhibitor.
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Page/Page column 126
(2008/06/13)
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- BENZOFURAN DERIVATIVE
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The present invention provides a benzofuran derivative of the formula [1]: wherein x is a group of the formula: -N="or" -CH=; Y is an optionally substituted amino group, an optionally substituted cycloalkyl group or an optionally substituted saturated heterocyclic group; A is a single bond, a carbon chain optionally having a double bond within or at the end(s) of the chain, or an oxygen atom; R1 is a hydrogen atom or a halogen atom; Ring B is an optionally substituted benzene ring; and R3 is a hydrogen atom, or a pharmaceutically acceptable salt thereof, which is useful as a medicament, especially as an activated blood coagulation factor X inhibitor.
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- POLYMER BOUND 4-DIALKYLAMINO PYRIDINES: SYNTHESYS, CHARACTERIZATION AND CATALYTIC EFFICIENCY.
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This work describes the synthesis of 4-carboxy-N-(4'-pyridino) piperidine (CPP), a functionalized analogue of the 4-dialkylamino pyridines, and its anchorage to various polymers by means of an amide bond.Some methods of titration of these supported CPP are pointed out.The efficiency of various supported CPP in the acetylation reaction of 1-methyl cyclohexanol are compared with DMAP as standard.The influence of various factors (polymer type, spacer, loading and temperature) are interpreted in relation to the nature of the microenvironment.An important decrease of the apparent pK of supported CPP as compared to DMAP (about 2 pK units) is assessed.
- Guendouz, Farida,Jacquier, Robert,Verducci, Jean
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p. 7095 - 7108
(2007/10/02)
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- CATALYSEURS D'ACYLATION SUPPORTES: SYNTHESE ET ACTIVITE D'AMINO-4 PYRIDINES FIXEES SUR POLYMERES
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New polystyrene-supported 4-amino pyridines are described.Some of them exhibit a good catalytic activity in acylation reactions.
- Guendouz, Farida,Jacquier, Robert
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p. 4521 - 4524
(2007/10/02)
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