title: 4-Aminopyrimidine tetrahydronaphthols: a series of novel vanilloid receptor-1 antagonists with improved solubility properties.
abstract: 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.
authors.affiliation: Department of Chemistry Research and Discovery, One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. edoherty@amgen.com
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Doherty
authors.forename: Daniel
authors.initials: D
authors.lastname: Retz
authors.forename: Narender R
authors.initials: NR
authors.lastname: Gavva
authors.forename: Rami
authors.initials: R
authors.lastname: Tamir
authors.forename: James J S
authors.initials: JJ
authors.lastname: Treanor
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
mesh_terms: 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*
chemical_list: 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