Abstract
Efforts to refine the SAR of the piperazinyl-glutamate-pyridines for more potent analogs with improved pharmacokinetic profiles are described. Exploring substituted piperidines and other ring systems at the 4-pyridyl position led to compounds with improved potency and pharmacokinetic properties over candidate I. In particular, compounds 4t and 5t were discovered with a 10-fold improvement over potency and improved pharmacokinetic profiles in both the rat and dog.
Copyright 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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CHO Cells
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Cricetinae
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Cricetulus
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Dogs
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Fibrinolytic Agents / chemical synthesis
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Fibrinolytic Agents / chemistry
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Fibrinolytic Agents / pharmacology*
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Glutamic Acid / chemical synthesis*
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Glutamic Acid / chemistry
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Glutamic Acid / pharmacology
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Humans
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Inhibitory Concentration 50
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Molecular Structure
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / pharmacology
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Platelet Aggregation / drug effects*
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Purinergic P2 Receptor Antagonists*
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology*
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Rats
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Receptors, Purinergic P2Y12
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Structure-Activity Relationship
Substances
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Fibrinolytic Agents
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P2RY12 protein, human
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P2ry12 protein, rat
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Piperidines
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Purinergic P2 Receptor Antagonists
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Pyridines
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Receptors, Purinergic P2Y12
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Glutamic Acid