Abstract
A series of novel, highly potent alpha(v)beta(3) antagonists based on a thiophene scaffold and containing an acylguanidine as an Arg-mimetic is described. A number of structural features, such as cyclic versus open guanidine and a variety of lipophilic side chains, carbamates, sulfonamides and beta-amino acids were explored with respect to inhibition of alpha(v)beta(3) mediated cell adhesion and selectivity versus alpha(IIb)beta(3) binding. In addition, compound 19 was found to be active in the TPTX model of osteoporosis.
MeSH terms
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Animals
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Binding Sites / drug effects
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Binding Sites / physiology
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Carbamates / chemistry
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Cell Adhesion / drug effects
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Cell Adhesion / physiology
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Cells, Cultured
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Guanidine / chemistry
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Osteoporosis / prevention & control*
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Parathyroidectomy
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Platelet Glycoprotein GPIIb-IIIa Complex / chemistry
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Platelet Glycoprotein GPIIb-IIIa Complex / metabolism*
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Rats
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Receptors, Vitronectin / antagonists & inhibitors*
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Receptors, Vitronectin / metabolism
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Sensitivity and Specificity
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Sulfonamides / chemistry
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Thiophenes / chemical synthesis
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Thiophenes / pharmacology
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Thyroidectomy
Substances
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Carbamates
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Platelet Glycoprotein GPIIb-IIIa Complex
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Receptors, Vitronectin
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Sulfonamides
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Thiophenes
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Guanidine