Abstract
A series of trisubstituted pyrimidines were synthesized to improve aqueous solubility of our first TRPV1 clinical candidate (1; AMG 517), while maintaining potent TRPV1 inhibitory activity. Structure-activity and structure-solubility studies led to the identification of compound 26. The aqueous solubility of 26 (>or=200microg/mL, 0.01 HCl; 6.7microg/mL, phosphate buffered saline (PBS); 150microg/mL, fasted-state simulated intestinal fluid (SIF)) was significantly improved over 1. In addition, compound 26 was found to be orally bioavailable (rat F(oral)=24%) and had potent TRPV1 antagonist activity (capsaicin IC(50)=1.5nM) comparable to that of 1.
MeSH terms
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Animals
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Benzothiazoles / chemistry
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Benzothiazoles / pharmacology
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CHO Cells
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Capsaicin / antagonists & inhibitors
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Cricetinae
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Cricetulus
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Drug Evaluation, Preclinical
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Hydrogen-Ion Concentration
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Piperazines / chemical synthesis
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Piperazines / pharmacology
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Solubility / drug effects
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Structure-Activity Relationship
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TRPV Cation Channels / antagonists & inhibitors*
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TRPV Cation Channels / biosynthesis
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TRPV Cation Channels / genetics
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TRPV Cation Channels / physiology
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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Piperazines
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Pyrimidines
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TRPV Cation Channels
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Trpv1 protein, rat
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Capsaicin