ABSTRACT
The synthesis and biological activity of novel glycoprotein IIb-IIla antagonists containing the 3,9-diazaspiro[5.5]undecane nucleus are described. The potent activity of these compounds as platelet aggregation inhibitors demonstrates the utility of the spirocyclic structures as a central template for nonpeptide RGD mimics.
Subject(s)
Platelet Aggregation Inhibitors/chemical synthesis , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Spiro Compounds/chemical synthesis , Administration, Oral , Animals , Aza Compounds/chemical synthesis , Aza Compounds/pharmacokinetics , Aza Compounds/pharmacology , Biological Availability , Blood Platelets/drug effects , Humans , Inhibitory Concentration 50 , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacology , Rats , Rats, Sprague-Dawley , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
The synthesis and biological activity of novel glycoprotein IIb-IlIa anatagonists containing 3-azaspiro[5.5]undec-9-yl nucleus are described. The potent activity of these compounds as platelet aggregation inhibitors demonstrates the utility of the monoazaspirocyclic structure as central template for nonpeptide RGD mimics.
Subject(s)
Platelet Aggregation Inhibitors/chemical synthesis , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Spiro Compounds/chemical synthesis , Administration, Oral , Animals , Aza Compounds/chemical synthesis , Aza Compounds/pharmacokinetics , Aza Compounds/pharmacology , Biological Availability , Blood Platelets/drug effects , Humans , Inhibitory Concentration 50 , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Vitronectin/antagonists & inhibitors , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
6-[4-Amidinobenzoyl]amino]-tetralone-2-acetic acid is a potent antagonist of GPIIb-IIIa. Substitution in the meta position of the benzamidine, or replacement with a heteroaryl amidine was tolerated in this series. Use of an acyl-linked 4-alkyl piperidine as an arginine isostere also provided active compounds. Compounds from this series provided substantial systemic exposure in the rat following oral administration.
Subject(s)
Acetates/metabolism , Amidines/metabolism , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Tetralones , Adenosine Diphosphate/pharmacology , Animals , Arginine/chemistry , Benzamidines/chemistry , Biological Availability , Drug Evaluation , Enzyme-Linked Immunosorbent Assay , Fibrinogen/metabolism , Humans , Inhibitory Concentration 50 , Models, Molecular , Platelet Aggregation/drug effects , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Prodrugs/chemical synthesis , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Protein Binding/drug effects , Protein Structure, Secondary , Rats , StereoisomerismABSTRACT
Disubstituted isoquinolones 2 and 3 have affinity for GPIIb-IIIa and represent leads for further structural evaluation. Structure-activity studies centered on the bicyclic beta-turn mimic contained in these molecules indicated that this moiety could accommodate a variety of modifications. Specifically, monocyclic, 6, 5-bicyclic, and 6,7-bicyclic structures provide compounds with affinity for GPIIb-IIIa. Within the 6,6-series, isoquinoline, tetralin, tetralone, and benzopyran nuclei yield potent antagonists that are specific for GPIIb-IIIa. Attachment of the arginine isostere (benzamidine) to the supporting nucleus can be accomplished with an ether or amide linkage, although the latter enhances activity. Several compounds in this series provided measurable blood levels after oral dosing. Conversion of the acid moiety in these molecules to an ester generally provided compounds which gave greater systemic exposure after oral administration. Absolute bioavailabilities in the rat for the ethyl ester prodrug derivatives of the tetralin, tetralone, and benzopyran analogues of 3 were 28%, 23%, and 24%, respectively.
