The de novo design and synthesis of cyclic urea inhibitors of factor Xa: initial SAR studies

R A Galemmo Jr; T P Maduskuie; C Dominguez; K A Rossi; R M Knabb; R R Wexler; P F Stouten

doi:10.1016/s0960-894x(98)00471-5

The de novo design and synthesis of cyclic urea inhibitors of factor Xa: initial SAR studies

Bioorg Med Chem Lett. 1998 Oct 6;8(19):2705-10. doi: 10.1016/s0960-894x(98)00471-5.

Authors

R A Galemmo Jr¹, T P Maduskuie, C Dominguez, K A Rossi, R M Knabb, R R Wexler, P F Stouten

Affiliation

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

PMID: 9873607
DOI: 10.1016/s0960-894x(98)00471-5

Abstract

In this report we discuss the design, synthesis, and validation of a novel series of cyclic urea inhibitors of the blood coagulation protein Factor Xa. This work culminates in compound 11, a monoamidine inhibitor of fXa employing a new S4 ligand that reduces the cationic character of these analogs. Compound 11 represents a lead for a series of more potent and selective inhibitors.

MeSH terms

Binding Sites
Drug Design
Factor Xa Inhibitors*
Hydrogen Bonding
Imidazoles / chemical synthesis
Imidazoles / pharmacology
Kinetics
Protein Conformation
Pyrimidinones / chemical synthesis
Pyrimidinones / pharmacology
Serine Proteinase Inhibitors / chemical synthesis*
Serine Proteinase Inhibitors / pharmacology*
Structure-Activity Relationship
Urea / analogs & derivatives*
Urea / chemistry
Urea / pharmacology

Substances

Factor Xa Inhibitors
Imidazoles
Pyrimidinones
Serine Proteinase Inhibitors
Urea