Abstract
A series of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives were synthesized and evaluated for their activity as VLA-4 antagonists. Of 22 compounds synthesized, 19 compounds showed potent activity with low nanomolar IC50 values. In addition, the representative compounds 11o and 11p with a hydroxy group in the pyrrolidine ring showed moderate plasma clearance in rats (11o, 30 ml/min/kg and 11p, 21 ml/min/kg) and in dogs (11o, 12 ml/min/kg and 11p, 9 ml/min/kg).
MeSH terms
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Acetates / chemical synthesis*
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Acetates / pharmacokinetics
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Acetates / pharmacology
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Animals
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Dogs
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Integrin alpha4beta1 / antagonists & inhibitors*
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Magnetic Resonance Spectroscopy
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Male
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Piperazines / chemical synthesis*
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Piperazines / pharmacokinetics
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Piperazines / pharmacology
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Piperidines / chemical synthesis*
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Piperidines / pharmacokinetics
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Piperidines / pharmacology
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Proline / analogs & derivatives*
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Proline / chemical synthesis
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Proline / pharmacokinetics
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Proline / pharmacology
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Rats
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Rats, Sprague-Dawley
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Spectrometry, Mass, Fast Atom Bombardment
Substances
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Acetates
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Integrin alpha4beta1
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Piperazines
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Piperidines
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prolyl-1-piperazinylacetic acid
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prolyl-4-piperidinylacetic acid
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Proline