Non-peptidic phenyl-based thrombin inhibitors: exploring structural requirements of the S1 specificity pocket with amidines

T Lu; B Tomczuk; R Bone; L Murphy; F R Salemme; R M Soll

doi:10.1016/s0960-894x(99)00616-2

Non-peptidic phenyl-based thrombin inhibitors: exploring structural requirements of the S1 specificity pocket with amidines

Bioorg Med Chem Lett. 2000 Jan 3;10(1):83-5. doi: 10.1016/s0960-894x(99)00616-2.

Authors

T Lu¹, B Tomczuk, R Bone, L Murphy, F R Salemme, R M Soll

Affiliation

¹ 3-Dimensional Pharmaceuticals, Eagleview Corporate Center, Exton, PA 19341, USA.

PMID: 10636250
DOI: 10.1016/s0960-894x(99)00616-2

Abstract

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.

MeSH terms

Amidines / chemistry*
Amidines / pharmacology
Antithrombins / chemistry*
Antithrombins / pharmacology*
Binding Sites
Hydrocarbons, Aromatic / chemistry
Hydrocarbons, Aromatic / pharmacology
Kinetics
Protein Conformation
Structure-Activity Relationship
Substrate Specificity
Thrombin / antagonists & inhibitors*
Thrombin / chemistry

Substances

Amidines
Antithrombins
Hydrocarbons, Aromatic
Thrombin