Active site-directed thrombin inhibitors--II. Studies related to arginine/guanidine bioisosteres

D R St Laurent; N Balasubramanian; W T Han; A Trehan; M E Federici; N A Meanwell; J J Wright; S M Seiler

doi:10.1016/0968-0896(95)00103-n

Active site-directed thrombin inhibitors--II. Studies related to arginine/guanidine bioisosteres

Bioorg Med Chem. 1995 Aug;3(8):1145-56. doi: 10.1016/0968-0896(95)00103-n.

Authors

D R St Laurent¹, N Balasubramanian, W T Han, A Trehan, M E Federici, N A Meanwell, J J Wright, S M Seiler

Affiliation

¹ Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492-7660, USA.

PMID: 7582986
DOI: 10.1016/0968-0896(95)00103-n

Abstract

A series of N-arylsulfonylarginine amides was synthesized wherein the guanidine or arginine moiety was isosterically replaced by a number of heterocyclic functionalities. These compounds were evaluated as potential active-site inhibitors of thrombin. Bisamidines 11a-n showed a similar SAR to that of simple arginine compounds. The ex vivo clotting time measurement of 11d after ip dosing showed prolongation of clotting time in rats.

Publication types

Comparative Study

MeSH terms

Animals
Antithrombins / chemical synthesis*
Antithrombins / chemistry
Antithrombins / pharmacology
Arginine*
Binding Sites
Blood Coagulation / drug effects
Drug Design
Guanidines*
Humans
Indicators and Reagents
Kinetics
Magnetic Resonance Spectroscopy
Molecular Structure
Rats
Serine Proteinase Inhibitors / chemical synthesis*
Serine Proteinase Inhibitors / chemistry
Serine Proteinase Inhibitors / pharmacology
Structure-Activity Relationship
Thrombin / antagonists & inhibitors*

Substances

Antithrombins
Guanidines
Indicators and Reagents
Serine Proteinase Inhibitors
Arginine
Thrombin