ABSTRACT
The use of 5,6-bicyclic amidines as arginine surrogates in the design of a novel class of potent platelet glycoprotein IIb-IIIa receptor (GPIIb-IIIa) antagonists is described. The additional conformational restriction offered by the bicyclic nucleus results in 20-400-fold increases in potency compared to the freely flexible, acyclic benzamidine counterpart. The design, synthesis, structure-activity relationships (SAR), and in vitro activity of this novel class of GPIIb-IIIa antagonists are presented.
Subject(s)
Arginine , Benzamidines/chemical synthesis , Benzamidines/pharmacology , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Benzamidines/chemistry , Enzyme-Linked Immunosorbent Assay , Fibrinogen/metabolism , Humans , Indicators and Reagents , Models, Molecular , Molecular Conformation , Molecular Structure , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
A systematic investigation of the structure-activity relationships of the C-3 side chain of the screening hit 1a led to the identification of the potent thrombin inhibitors 23c, 28c, and 31c. Their activities (1240, 903, and 1271 x 10(6) L/mol, respectively) represent 2200- and 2900-fold increases in potency over the starting lead 1a. This activity enhancement was accomplished with an increase of thrombin selectivity. The in vitro anticoagulant profiles of derivatives 28c and 31c were determined, and they compare favorably with the clinical agent H-R-1-[4aS, 8aS]perhydroisoquinolyl-prolyl-arginyl aldehyde (D-Piq-Pro-Arg-H; 32). The more potent members of this series have been studied in an arterial/venous shunt (AV shunt) model of thrombosis and were found to be efficacious in reducing clot formation. However, their efficacy is currently limited by their rapid and extensive distribution following administration.
Subject(s)
Anticoagulants/chemical synthesis , Pyrrolidines/chemical synthesis , Serine Proteinase Inhibitors/chemical synthesis , Thiophenes/chemical synthesis , Thrombin/antagonists & inhibitors , Animals , Anticoagulants/chemistry , Anticoagulants/pharmacokinetics , Anticoagulants/pharmacology , Binding Sites , Crystallography, X-Ray , Drug Evaluation, Preclinical , Humans , In Vitro Techniques , Models, Molecular , Pyrrolidines/chemistry , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Rats , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacokinetics , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacokinetics , Thiophenes/pharmacology , Thrombosis/blood , Thrombosis/metabolismABSTRACT
Quantitative structure activity analysis was applied to two series of dihydropyridine (DHP) calcium channel blocking agents. One series of compounds was composed of DHPs substituted in the 4-position with an ortho or meta nitro substituted phenyl ring. The second group consisted of DHPs substituted at the 4-position with a novel thieno [3,2-c] pyridine ring. Both series consisted of compounds with unsymmetrical ester substitutions on the dihydropyridine ring. The antihypertensive activity of the compounds were determined in a spontaneously hypertensive rat model. Regression analysis indicated the antihypertensive activity of an i.v. dose correlated with the calculated octanol/water coefficent (clogP). Regression analysis did not find correlation with the in vitro potency and the clogP values.
Subject(s)
Blood Pressure/drug effects , Calcium Channel Blockers/pharmacology , Dihydropyridines/pharmacology , Animals , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/chemistry , Dihydropyridines/chemical synthesis , Dihydropyridines/chemistry , Dogs , Female , Injections, Intravenous , Male , Models, Biological , Muscle Relaxation/drug effects , Muscle, Smooth, Vascular/drug effects , Rats , Rats, Inbred SHR , Regression Analysis , Structure-Activity RelationshipABSTRACT
A novel series of benzo[b]thiophene diamine thrombin inhibitors with a conformationally restricted C3-side chain 3 was investigated. The constrained C3-side chain by a cyclohexyl ring contributed to not only an additive but also a synergistic effect on the thrombin inhibitory activity. The SAR studies resulted in the discovery of a potent thrombin inhibitor 27 that was over 750-fold more potent than the initial lead compound 1.
Subject(s)
Thiophenes/chemistry , Thrombin/antagonists & inhibitors , Structure-Activity Relationship , Thiophenes/pharmacologyABSTRACT
The preparation and biological evaluation of a series of benzo[b]thiophene diamine thrombin inhibitors possessing conformationally restricted C-4" linkers are reported. Compared to the parent compounds 1a/b, the unsaturated derivatives 3a/b exhibited a modest twofold increase in thrombin inhibitory activity, while the more lipophilic carbocyclic ring containing analogs 4a/b affected an eightfold enhancement in potency.
Subject(s)
Antithrombins/pharmacology , Thiophenes/pharmacology , Antithrombins/chemistry , Binding Sites , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Structure , Thiophenes/chemistryABSTRACT
Potent, subnanomolar thrombin inhibitors 4, 5, and 6 are developed through side chain optimization of novel, benzo[b]thiophene-based small organic entities 2 and 3 and through SAR additivity studies of the new structural elements identified. X-ray crystallographic studies of 4b-thrombin complex revealed a hydrophobic and an electrostatic interaction of these new elements with thrombin at the S2 and S3 binding sites. In vitro and in vivo pharmacological studies showed that 4, 5, and 6 are potent anticoagulants in human plasma with demonstrated antithrombotic efficacy in a rat model of thrombosis.