Abstract
Clinical candidate AMG 517 (1) is a potent antagonist toward multiple modes of activation of TRPV1; however, it suffers from poor solubility. Analogs with various substituents at the R region of 3 were prepared to improve the solubility while maintaining the potent TRPV1 activity of 1. Compounds were identified that maintained potency, had good pharmacokinetic properties, and improved solubility relative to 1.
MeSH terms
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Animals
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Benzothiazoles / pharmacokinetics
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Benzothiazoles / pharmacology*
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Combinatorial Chemistry Techniques
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Molecular Structure
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Pyrimidines / chemical synthesis
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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TRPV Cation Channels / antagonists & inhibitors*
Substances
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Benzothiazoles
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N-(4-(6-(4-trifluoromethylphenyl)pyrimidin-4-yloxy)benzothiazol-2-yl)acetamide
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Pyrimidines
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TRPV Cation Channels
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Trpv1 protein, rat