Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 21, Pages 8696-8711Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm401169a
Keywords
-
Categories
Funding
- Italian Ministry for Education Universities and Research (MIUR, Rome, Italy) [2007T9HTFB_003]
Ask authors/readers for more resources
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-ilia activity and artificial membrane permeability were considerably improved by optimizing the basic PI 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 (K-i = 6 nM), weak anti-Xa activity (K-i = 5.64 mu M), 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).
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available