compounds for treating neurodegenerative …

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1、COMPOUNDSFORTREATINGNEURODEGENERATIVEDISEASESBACKGROUNDOFTHEINVENTION[0001]FIELDOFTHEINVENTION[0002]Thepresentinventionrelatestoorganiccompoundsusefulforinhibitionofβ-secretaseenzymaticactivityandthetherapyand/orprophylaxisofneurodegenerativediseasesassociatedtherewith.Moreparticularl

2、y,certainspirotetrahyrdonaphthalenecompoundsusefulinthetreatmentandpreventionofneurodegenerativediseases,suchasAlzheimer'sdisease,areprovidedherein.[0003]DESCRIPTIONOFTHESTATEOFTHEART[0004]Alzheimer'sdisease(AD)isaneurologicaldisorderthoughttobeprimarilycausedbyamyloidplaques,anaccumu

3、lationofabnormalproteindepositsinthebrain.Itisbelievedthatanincreaseintheproductionandaccumulationofamyloidbetapeptides(alsoreferredtoasAβorA-beta)inplaquesleadstonervecelldeath,whichcontributestothedevelopmentandprogressionofAD.Lossofnervecellsduetoamyloidplaquesinstrategicbrainareas

4、,inturn,causesreductionintheneurotransmittersandimpairmentofmemory.Theproteinsprincipallyresponsiblefortheplaquebuildupincludeamyloidprecursorprotein(APP)andpresenilinIandII(PSIandPSII).MutationsineachofthesethreeproteinshavebeenobservedtoenhanceproteolyticprocessingofAPPviaanintracel

5、lularpathwaythatproducesAβpeptidesrangingfrom39to43aminoacids.TheAβ1-42fragmenthasaparticularlyhighpropensityofformingaggregatesduetotwoveryhydrophobicaminoacidresiduesatitsC-terminus.Thus,Aβ1-42fragmentisbelievedtobemainlyresponsiblefortheinitiationofneuriticamyloidplaqueformationinA

6、Dandisthereforeactivelybeingpursuedasatherapeutictarget.Anti-AβantibodieshavebeenshowntoreversethehistologicandcognitiveimpairmentsinmicewhichoverexpressAβandarecurrentlybeingtestedinhumanclinicaltrials.Effectivetreatmentrequiresanti-Aβantibodiestocrosstheblood-brainbarrier(BBB),howev

7、er,antibodiestypicallycrosstheBBBverypoorlyandaccumulateinthebraininlowconcentration.[0005]DifferentformsofAPPrangeinsizefrom695-770aminoacids,localizetothecellsurface,andhaveasingleC-terminaltransmembranedomain.AβisderivedfromaregionofAPPadjacenttoandcontainingaportionofthetransmembr

8、anedo