Novel vanilloid receptor-1 antagonists: 2. Structure-activity relationships of 4-oxopyrimidines leading to the selection of a clinical candidate.
A series of novel 4-oxopyrimidine TRPV1 antagonists was evaluated in assays measuring the blockade of capsaicin or acid-induced influx of calcium into CHO cells expressing TRPV1. The investigation of the structure-activity relationships in the heterocyclic A-region revealed the optimum pharmacophoric elements required for activity in this series and resulted in the identification of subnanomolar TRPV1 antagonists. The most potent of these antagonists were thoroughly profiled in pharmacokinetic assays. Optimization of the heterocyclic A-region led to the design and synthesis of 23, a compound that potently blocked multiple modes of TRPV1 activation. Compound 23 was shown to be effective in a rodent "on-target" biochemical challenge model (capsaicin-induced flinch, ED50 = 0.33 mg/kg p.o.) and was antihyperalgesic in a model of inflammatory pain (CFA-induced thermal hyperalgesia, MED = 0.83 mg/kg, p.o.). Based on its in vivo efficacy and pharmacokinetic profile, compound 23 (N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide; AMG 517) was selected for further evaluation in human clinical trials.
Doherty
Elizabeth M
EM
Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA.
Fotsch
Christopher
C
Bannon
Anthony W
AW
Bo
Yunxin
Y
Chen
Ning
N
Dominguez
Celia
C
Falsey
James
J
Gavva
Narender R
NR
Katon
Jodie
J
Nixey
Thomas
T
Ognyanov
Vassil I
VI
Pettus
Liping
L
Rzasa
Robert M
RM
Stec
Markian
M
Surapaneni
Sekhar
S
Tamir
Rami
R
Zhu
Jiawang
J
Treanor
James J S
JJ
Norman
Mark H
MH
D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004355:Drug Stability; D000882:Haplorhini; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010147:Pain Measurement; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics
D000700:Analgesics; 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; D002118:Calcium