- 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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- 1, 4-DISUBSTITUTED PIPERIDINES AS VASOPRESSIN RECEPTOR VIA ANTAGONISTS
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The present invention provides compounds of formula (1) compositions comprising such compounds; the use of such compounds in therapy (such as in the treatment of dysmenorrhoea); and methods of treating patients with such compounds; wherein A and G are as defined herein.
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Page/Page column 39
(2010/09/17)
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- Synthesis and pharmacological evaluation of a new class of 2-oxo-8- azaspiro (4,5)decan-1-ones as analogues of the muscarinic agonist RS-86
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A new series of 8-substituted-2-oxo-8-azapsiro (4,5)decan-1-ones has been synthesized and compounds tested for their cholinergic properties in comparison with the muscarinic agonist RS-86. Preliminary in vitro and in vivo pharmacological data indicate that none of them is provided with significant cholinergic effects either at central or peripheral level. A possible explanation for the lack of activity is given on the basis of conformational studies.
- Cignarella,Villa,Barlocco
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p. 1439 - 1445
(2007/10/02)
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- Cerebral function enhancing diazinylpiperidine derivatives
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A series of diazinylpiperidine compounds of Formula I STR1 wherein X is an ethylene chain or a 1,2-benzo ring; Y is carbonyl or methylene; R1 is hydrogen or lower alkyl; and Z is an R2, R3 -disubstituted diazinyl ring selected from pyridazine, pyrimidine, and pyrazine ring systems. Pharmacologic and neuroanatomical testing demonstrates that compounds of the series act to enhance cerebral function in mammals, particularly when there is a deficit in normal cerebral functioning. Specific pharmacologic test results indicate that compounds of Formula I possess cognition and memory enhancing activity.
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