ABSTRACT
In an effort to discover potent, clinically useful thrombin inhibitors, a rapid analogue synthetic approach was used to explore the P(1) region. Various benzylamines were coupled to a pyridine/pyrazinone P(2)-P(3) template. One compound with an o-thiadiazole benzylic substitution was found to have a thrombin K(i) of 0.84 nM. A study of ortho-substituted five-membered-ring heterocycles was undertaken and subsequently demonstrated that the o-triazole and tetrazole rings were optimal. Combination of these potent P(1) aryl heterocycles with a variety of P(2)-P(3) groups produced a compound with an extraordinary thrombin inhibitory activity of 1.4 pM. It is hoped that this potency enhancement in P(1) will allow for more diversification in the P(2)-P(3) region to ultimately address additional pharmacological concerns.
Subject(s)
Heterocyclic Compounds/chemical synthesis , Thrombin/antagonists & inhibitors , Benzylamines/chemical synthesis , Benzylamines/chemistry , Binding Sites , Heterocyclic Compounds/chemistry , Models, Molecular , Pyrazines/chemical synthesis , Pyrazines/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity Relationship , Tetrazoles/chemical synthesis , Tetrazoles/chemistry , Thiadiazoles/chemical synthesis , Thiadiazoles/chemistry , Thrombin/chemistry , Triazoles/chemical synthesis , Triazoles/chemistryABSTRACT
SUMMARY: Efficacy of a new, potent non-selective endothelin antagonist, l-753037, was examined in a model of canine coronary artery occlusion and reperfusion to assess whether blockade of both ETA and ETB receptors would enhance or reduce myocardial ischemic injury. Instrumented dogs were randomized to receive vehicle (n = 9) or l-753037 (0.1 microg/kg/min, n = 9) by intracoronary infusion 30 minutes before a 90-minute LCx coronary artery occlusion and through 4 hours of reperfusion. After 4 hours of reperfusion, plasma ET-1 levels rose significantly in both groups: 24 +/- 3 fmol/ml in vehicle animals (P < 0.01) versus 42 +/- 5 fmol/ml with l-753037 (P < 0.05). Treatment with l-753037 normalized total LCx flow and regional myocardial flow after 4 hours of reperfusion in all regions. LCx flow was reduced 16% from pre-occlusion baseline (P = 0.45) with treatment compared with 35% with vehicle (P < 0.01). Endocardial flow in the risk region returned to baseline values with l-753037 treatment but was reduced approximately 50% in vehicle animals. l-753037 treatment was associated with a 38% reduction in infarct size (24.1 +/- 3.9% AAR with l-753037 treatment versus 38.7 +/- 3.1% with vehicle, P < 0.01). Thus, a non-selective endothelin antagonist provides significant myocardial protection primarily by improving regional myocardial flow distribution following reperfusion and demonstrated no detrimental effects associated with blockade of the ETB receptor.
Subject(s)
Endothelin Receptor Antagonists , Myocardial Ischemia/prevention & control , Myocardial Reperfusion Injury/prevention & control , Pyridines/therapeutic use , Animals , Coronary Disease/blood , Coronary Disease/therapy , Dogs , Receptors, Endothelin/bloodABSTRACT
We describe a series of highly potent and efficacious thrombin inhibitors based on a 3-amino-4-sulfonylpyridinone acetamide template. The functionally dense sulfonyl group stabilizes the aminopyridinone, conformationally constrains the 4-substituent, and forms a hydrogen bond to the insertion loop tyrosine OH. We also describe a related series of fused bicyclic dihydrothiadiazinedioxide derivatives, of which one had improved pharmacokinetics in dogs after oral dosing.
Subject(s)
Acetamides/chemistry , Acetamides/pharmacology , Pyridones/chemistry , Pyridones/pharmacology , Thiadiazines/chemistry , Thiadiazines/pharmacology , Thrombin/antagonists & inhibitors , Acetamides/pharmacokinetics , Administration, Oral , Animals , Disease Models, Animal , Dogs , Ferric Compounds/toxicity , Humans , Models, Molecular , Pyridones/pharmacokinetics , Rats , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacokinetics , Sulfones/pharmacology , Thiadiazines/pharmacokinetics , Thrombosis/chemically induced , Trypsin Inhibitors/chemistry , Trypsin Inhibitors/pharmacokinetics , Trypsin Inhibitors/pharmacologyABSTRACT
In this manuscript we demonstrate that a modification principally directed toward the improvement of the aqueous solubility (i.e., introduction a P3 pyridine N-oxide) of the previous lead compound afforded a new series of potent orally bioavailable P1 N-benzylamide thrombin inhibitors. An expedited investigation of the P1 SAR with respect to oral bioavailability, plasma half-life, and human liver microsome stability revealed 5 as the best candidate for advanced evaluation.
Subject(s)
Acetamides/chemical synthesis , Acetamides/pharmacology , Pyrazines/chemical synthesis , Pyrazines/pharmacology , Pyridines/chemistry , Thrombin/antagonists & inhibitors , Animals , Biological Availability , Chemical Phenomena , Chemistry, Physical , Crystallography, X-Ray , Dogs , Half-Life , Humans , In Vitro Techniques , Injections, Intravenous , Macaca mulatta , Microsomes, Liver/metabolism , Models, Molecular , Oxides/chemistry , Rats , Solubility , Structure-Activity Relationship , Thrombosis/chemically induced , Thrombosis/drug therapyABSTRACT
Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.
