http://chineseinput.net/에서 pinyin(병음)방식으로 중국어를 변환할 수 있습니다.
변환된 중국어를 복사하여 사용하시면 됩니다.
Kim, Myeong Seop,Ryu, HyungChul,Kang, Dong Wook,Cho, Seong-Hee,Seo, Sejin,Park, Young Soo,Kim, Mi-Yeon,Kwak, Eun Joo,Kim, Yong Soo,Bhondwe, Rahul S.,Kim, Ho Shin,Park, Seul-gi,Son, Karam,Choi, Sun,DeA American Chemical Society 2012 Journal of medicinal chemistry Vol.55 No.19
<P>A series of <I>N</I>-(2-amino-6-trifluoromethylpyridin-3-ylmethyl)-2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were designed combining previously identified pharmacophoric elements and evaluated as hTRPV1 antagonists. The SAR analysis indicated that specific hydrophobic interactions of the 2-amino substituents in the C-region of the ligand were critical for high hTRPV1 binding potency. In particular, compound <B>49</B><I><B>S</B></I> was an excellent TRPV1 antagonist (<I>K</I><SUB>i(CAP)</SUB> = 0.2 nM; IC<SUB>50(pH)</SUB> = 6.3 nM) and was thus approximately 100- and 20-fold more potent, respectively, than the parent compounds <B>2</B> and <B>3</B> for capsaicin antagonism. Furthermore, it demonstrated strong analgesic activity in the rat neuropathic model superior to <B>2</B> with almost no side effects. Compound <B>49</B><I><B>S</B></I> antagonized capsaicin induced hypothermia in mice but showed TRPV1-related hyperthermia. The basis for the high potency of <B>49</B><I><B>S</B></I> compared to <B>2</B> is suggested by docking analysis with our hTRPV1 homology model in which the 4-methylpiperidinyl group in the C-region of <B>49</B><I><B>S</B></I> made additional hydrophobic interactions with the hydrophobic region.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2012/jmcmar.2012.55.issue-19/jm300780p/production/images/medium/jm-2012-00780p_0014.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jm300780p'>ACS Electronic Supporting Info</A></P>