<P><B>Abstract</B></P> <P>We investigated a series of uracil analogues by introducing various substituents on the phenyl ring of the <I>N</I>-3 aminoethyl side chain and evaluated their antagonistic activity ...
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https://www.riss.kr/link?id=A107707998
2018
-
SCOPUS,SCIE
학술저널
413-424(12쪽)
0
상세조회0
다운로드다국어 초록 (Multilingual Abstract)
<P><B>Abstract</B></P> <P>We investigated a series of uracil analogues by introducing various substituents on the phenyl ring of the <I>N</I>-3 aminoethyl side chain and evaluated their antagonistic activity ...
<P><B>Abstract</B></P> <P>We investigated a series of uracil analogues by introducing various substituents on the phenyl ring of the <I>N</I>-3 aminoethyl side chain and evaluated their antagonistic activity against human gonadotropin-releasing hormone (GnRH) receptors. Analogues with substituents at the ortho or meta position demonstrated potent in vitro antagonistic activity. Specifically, the introduction of a 2-OMe group enhanced nuclear factor of activated T-cells (NFAT) inhibition up to 6-fold compared to the unsubstituted analogue. We identified compound <B>12c</B> as a highly potent GnRH antagonist with moderate CYP inhibition. Compound <B>12c</B> showed potent and prolonged LH suppression after a single dose was orally administered in castrated monkeys compared to a known antagonist, Elagolix. We believe that our SAR study offers useful insights to design GnRH antagonists as a potential treatment option for endometriosis.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A series of 3-(2-aminoethyl) uracil analogues were synthesized as GnRH antagonists. </LI> <LI> Compound <B>12c</B> showed highly potent GnRH antagonism with moderate CYP inhibition. </LI> <LI> Compound <B>12c</B> exhibited potent and prolonged LH suppression in castrated monkeys. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>