Non-peptidic phenyl-based thrombin inhibitors: exploring structural requirements of the S1 specificity pocket with amidines.
We expand the structural requirements and structure-activity relationship of a novel class of non-peptidic aryl-based thrombin inhibitors through exploration of the S1 specificity pocket of thrombin using flexible and constrained amidines. The most active compound of this class is 11 with Ki = 69 nM, which is ca. 15-fold less potent than constrained guanidine 5.
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3-Dimensional Pharmaceuticals, Eagleview Corporate Center, Exton, PA 19341, USA.
Tomczuk
B
B
Bone
R
R
Murphy
L
L
Salemme
F R
FR
Soll
R M
RM
D000578:Amidines / Q000737:chemistry* / Q000494:pharmacology; D000991:Antithrombins / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D006841:Hydrocarbons, Aromatic / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000578:Amidines; D000991:Antithrombins; D006841:Hydrocarbons, Aromatic; D013917:Thrombin