- Derivatives of quinoline as inhibitors for MEK
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1. A compound of formula (I) or a pharmaceutically acceptable salt thereof. wherein: n is 0-1; X and Y are independently selected from -NH-, -O-, -S-, or -NR8- where R8 is alkyl of 1-6 carbon atoms and X may additionally comprise a CH2 group; R7 is a group (CH2)mR9 where m is 0,or an integer of from 1-3 and R9 is a substituted aryl group, an optionally substituted cycloalkyl ring of up to 10 carbon atoms, or an optionally substituted heterocyclic ring or an N-oxide of any nitrogen containing ring; R6 is a divalent cycloalkyl of 3 to 7 carbon atoms, which may be optionally further substituted with one or more alkyl of 1 to 6 carbon atom groups; or is a divalent pyridinyl, pyimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionally further substituted with one or more specified groups; R1, R2, R3 and R4 are each independently selected from hydrogen or various specified organic groups. Compounds are useful as pharmaceuticals for the inhibition of MEK activity.
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Page/Page column 79
(2010/02/14)
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- Synthesis and structure-activity relationships of phenoxypyridine derivatives as novel inhibitors of the sodium-calcium exchanger
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A series of 2-phenoxypyridine derivatives were prepared and evaluated for their inhibitory activity against the reverse and forward modes of the sodium-calcium exchanger (NCX). The structure-activity relationships of these compounds on the inhibitory activity for the sodium-calcium exchanger are discussed. The sodium-calcium exchanger (NCX) is known as the transporter that controls the concentration of Ca2+ in cardiac myocytes. In the setting of heart failure and myocardial ischemia-reperfusion, NCX underlies an arrhythmogenic transient inward current responsible for delayed after-depolarizations and nonreentrant initiation of ventricular tachycardia. NCX is an attractive target for treatment in heart failure and myocardial ischemia-reperfusion. We have designed and synthesized a series of phenoxypyridine derivatives, based on compound 3. These derivatives have been evaluated for their inhibitory activity against both the reverse and forward mode of NCX in CCL39 cells. We have discovered several novel potent NCX inhibitors (39q, 48k), which have a high selectivity for reverse NCX inhibitory activity.
- Kuramochi, Takahiro,Kakefuda, Akio,Yamada, Hiroyoshi,Sato, Ippei,Taguchi, Taku,Sakamoto, Shuichi
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p. 5039 - 5056
(2007/10/03)
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