4-Aminopyrimidine tetrahydronaphthols: a series of novel vanilloid receptor-1 antagonists with improved solubility properties.
8-(6-(4-(Trifluoromethyl)phenyl)pyrimidin-4-ylamino)-1,2,3,4-tetrahydronaphthalen-2-ol (4) and analogs (5-10) were shown to be potent inhibitors of human and rat TRPV1 in vitro with increased solubility over our previous series. Synthesis, SAR, and improvements in metabolic stability and absorption of these compounds are described herein.
Doherty
Elizabeth M
EM
Department of Chemistry Research and Discovery, One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. edoherty@amgen.com
Retz
Daniel
D
Gavva
Narender R
NR
Tamir
Rami
R
Treanor
James J S
JJ
Norman
Mark H
MH
D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D001783:Blood Flow Velocity / Q000187:drug effects; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003412:Cricetulus; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008657:Metabolic Clearance Rate; D015394:Molecular Structure; D009284:Naphthols / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*
D052160:Benzothiazoles; C523409:N-(4-(6-(4-trifluoromethylphenyl)pyrimidin-4-yloxy)benzothiazol-2-yl)acetamide; D009284:Naphthols; D011743:Pyrimidines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493922:Trpv1 protein, rat; D002211:Capsaicin; D002118:Calcium