The structure activity relationships of a novel series of non-amide-based thrombin inhibitors are described. Exploration of the P2 and the aryl binding region for this series has identified optimal groups for achieving nanomolar potency. The binding modes of these optimal groups have been confirmed by X-ray structural analysis.
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Structure-activity and crystallographic analysis of a new class of non-amide-based thrombin inhibitor.
Bioorg Med Chem Lett
January 2000
3-Dimensional Pharmaceutical, Inc., Eagleview Corporate Center, Exton, PA 19341, USA.
The structure activity relationships of a novel series of non-amide-based thrombin inhibitors are described. Exploration of the P2 and the aryl binding region for this series has identified optimal groups for achieving nanomolar potency. The binding modes of these optimal groups have been confirmed by X-ray structural analysis.
View Article and Find Full Text PDFAmidinohydrazones as guanidine bioisosteres: application to a new class of potent, selective and orally bioavailable, non-amide-based small-molecule thrombin inhibitors.
Bioorg Med Chem Lett
January 2000
3-Dimensional Pharmaceuticals, Eagleview Corporate Center, Exton, PA 19341, USA.
We describe a new class of potent, non-amide-based small molecule thrombin inhibitors in which an amidinohydrazone is used as a guanidine bioisostere on a non-peptide scaffold. Compound 4 exhibits nM inhibition of thrombin, is selective for thrombin, and shows 60 and 23% bioavailability in rabbits and dogs, respectively. Crystallographic analysis of 4 bound to thrombin confirmed the amindinohydrazone binding mode.
View Article and Find Full Text PDFWe describe the in vitro evaluation and crystallographic analysis of a new class of potent and selective, non-amino acid-based, small-molecule thrombin inhibitors, exemplified by 14. This class of achiral inhibitors lacks an amide-based backbone, exhibits nM inhibition of thrombin, and is selective for thrombin. Compound 14 does not interact with the active-site catalytic apparatus and is anchored to the enzyme via a single network of hydrogen bonds to Asp189 of the S1 pocket.
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