Design and synthesis of potent and selective 5,6-fused heterocyclic thrombin inhibitors

C Dominguez; D E Duffy; Q Han; R S Alexander; R A Galemmo Jr; J M Park; P C Wong; E C Amparo; R M Knabb; J Luettgen; R R Wexler

doi:10.1016/s0960-894x(99)00113-4

Design and synthesis of potent and selective 5,6-fused heterocyclic thrombin inhibitors

Bioorg Med Chem Lett. 1999 Apr 5;9(7):925-30. doi: 10.1016/s0960-894x(99)00113-4.

Authors

C Dominguez¹, D E Duffy, Q Han, R S Alexander, R A Galemmo Jr, J M Park, P C Wong, E C Amparo, R M Knabb, J Luettgen, R R Wexler

Affiliation

¹ DuPont Pharmaceuticals Company, Wilmington, DE 19880-0500, USA.

PMID: 10230612
DOI: 10.1016/s0960-894x(99)00113-4

Abstract

Thrombin, a serine protease, plays a central role in the initiation of thrombotic events. We report the design, synthesis, and antithrombotic efficacy of XU817 (7), a nonpeptide 5-(amidino) indole thrombin inhibitor. Utilizing the co-crystal structure of XU817 bound in the active site of thrombin we were able to synthesize analogs with enhanced thrombin affinity.

MeSH terms

Amidines / chemical synthesis
Amidines / chemistry*
Amidines / pharmacology
Animals
Antithrombins / chemical synthesis
Antithrombins / chemistry*
Antithrombins / pharmacology
Drug Design
Heterocyclic Compounds / chemical synthesis
Heterocyclic Compounds / chemistry*
Heterocyclic Compounds / pharmacology
Hydrogen Bonding
Indoles / chemical synthesis
Indoles / chemistry*
Indoles / pharmacology
Molecular Structure
Rats

Substances

Amidines
Antithrombins
Heterocyclic Compounds
Indoles
XU 817