Substituted aryl pyrimidines as potent and soluble TRPV1 antagonists.
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.
Stec
Markian M
MM
Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. mstec@amgen.com
Bo
Yunxin
Y
Chakrabarti
Partha P
PP
Liao
Lillian
L
Ncube
Mqhele
M
Tamayo
Nuria
N
Tamir
Rami
R
Gavva
Narender R
NR
Treanor
James J S
JJ
Norman
Mark H
MH
D000818:Animals; D052160:Benzothiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; 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; D011743:Pyrimidines; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat