A new synthetic protocol has been developed to provide entry into a series of novel tricyclic aryltriazole-3-thiones analogs. The classical reaction conditions of subjecting an arylhydrazide with ...thiophosgene to form the thioisocyanate intermediate and ultimately the corresponding aryltriazole-3-thione framework were not successful. However, using a combination of carbon disulfide and 1,8-diazabicyclo5.4.0undec-7-ene (DBU) to form the thioisocyanate intermediate was found to produce the novel tricyclic aryltriazole-3-thiones (5, 8a-c) in good yield.
Utilizing X-ray crystallography and molecular modeling, highly potent and selective peptidomimetic thrombin inhibitors have been designed containing a rigid piperazinedione template. The synthesis ...and biological activity of these compounds will be described.
Herein, we report the discovery of novel, proline-based factor Xa inhibitors containing a neutral P1 chlorophenyl pharmacophore. Through the additional incorporation of ...1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one 22, as a P4 pharmacophore, we discovered compound 7 (PD 0348292). This compound is a selective, orally bioavailable, efficacious FXa inhibitor that is currently in phase II clinical trials for the treatment and prevention of thrombotic disorders.
The synthesis and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors is described. We have explored the SAR with modifications to the P1 site. The introduction of arginine ...mimetics at the P1 site led to potent and selective thrombin inhibitors.
The synthesis, and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors are described. We have explored the SAR with modifications to the P1 site. The introduction of arginine mimetics at the P1 site led to potent and selective thombin inhibitors.
Peptidomimetic inhibitors of general structure
1 have been prepared. Optimization of the binding affinities of these compounds through variation of the P3 hydrophobic residue is described. Selected ...substituted bicylic lactams displayed interesting pharmacological profiles both in vitro and in vivo.
Design, synthesis, and SAR of low molecular weight peptidomimetic inhibitors of thrombin are described.
The synthesis and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors are described. We have explored the SAR around the P1′ site. Modification of the P1′ site has been ...found to affect potency and selectivity.
The synthesis and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors are described. We have explored the SAR around the P1′ site. Modification of the P1′ site has been found to affect potency and selectivity.
Potent and selective thrombin inhibitors have been prepared with a piperazinedione template and L-amino acids. Likewise, incorporation of D-amino acids led to potent inhibitors with a novel mode of ...binding. Herein, the structure activity relationships and structural aspects of these compounds will be described.
Endothelin-1 is a potent vasoconstrictor which is thought to be involved in many human disease states. We have developed a series of indole non-peptide endothelin antagonists which display nanomolar ...receptor affinity. The representative compound from this series is PD 159433 (
22), an ET
A selective antagonist with an IC
50 of 2 nM. The discovery, synthesis and structure-activity relationships of this series of compounds are described.
The discovery, synthesis, and structure-activity relationships of a series of endothelin antagonists are described.
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