In vitro evaluation and crystallographic analysis of a new class of selective, non-amide-based thrombin inhibitors.
We 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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T
T
3-Dimensional Pharmaceuticals, Exton, PA 19341, USA.
Tomczuk
B
B
Illig
C R
CR
Bone
R
R
Murphy
L
L
Spurlino
J
J
Salemme
F R
FR
Soll
R M
RM
D000577:Amides / Q000737:chemistry; D000991:Antithrombins / Q000737:chemistry / Q000494:pharmacology*; D003461:Crystallography; D004341:Drug Evaluation; D006860:Hydrogen Bonding; D015394:Molecular Structure
D000577:Amides; D000991:Antithrombins