Identification and biological evaluation of 4-(3-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid (5-trifluoromethylpyridin-2-yl)amide, a high affinity TRPV1 (VR1) vanilloid receptor antagonist

被引:161
作者
Swanson, DM
Dubin, AE
Shah, C
Nasser, N
Chang, L
Dax, SL
Jetter, M
Breitenbucher, JG
Liu, CL
Mazur, C
Lord, B
Gonzales, L
Hoey, K
Rizzolio, M
Bogenstaetter, M
Codd, EE
Lee, DH
Zhang, SP
Chaplan, SR
Carruthers, NI
机构
[1] Johnson & Johnson Pharmaceut Res & Dev LLC, San Diego, CA 92121 USA
[2] Johnson & Johnson Pharmaceut Res & Dev LLC, Spring House, PA 19477 USA
关键词
D O I
10.1021/jm0495071
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
High throughput screening using the recombinant human TRPV1 receptor was used to identify a series of pyridinylpiperazine ureas (3) as TRPV1 vanilloid receptor ligands. Exploration of the structure-activity relationships by parallel synthesis identified the essential pharmacophoric elements for antagonism that permitted further optimization via targeted synthesis to provide a potent orally bioavailable and selective TRPV1 modulator 41 active in several in vivo models.
引用
收藏
页码:1857 / 1872
页数:16
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