Potent and selective class IIa HDAC tetrasubstituted cyclopropane hydroxamic acid inhibitors were identified with high oral bioavailability that exhibited good brain and muscle exposure. Compound 14 displayed suitable properties for assessment of the impact of class IIa HDAC catalytic site inhibition in preclinical disease models.KEYWORDS: Class IIa HDAC inhibitors, hydroxamic acid, CNS exposure, tetrasubstituted cyclopropane, cyclopropanation, Huntington's disease I nhibition of class IIa HDAC enzymes has been suggested as a therapeutic strategy for a number of indications, including Huntington's disease (HD) and muscular atrophy. Class IIa HDACs are large proteins with multiple functions including transcription factor binding and N-acetyl lysine recognition. 1,2 Of most interest to our laboratory is the role of class IIa HDAC biology in HD, in particular the beneficial effect, which has been observed following HDAC4 genetic suppression. 3−5 Replication of these effects in preclinical models of HD via occupancy of the class IIa HDAC catalytic domain would provide a rationale for small molecule therapy. Currently there are no marketed HDAC class IIa-selective inhibitors, whereas four pan-HDAC inhibitors, vorinostat (SAHA), romidepsin, belinostat, and panobinostat are on the market.Class IIa-selective HDAC inhibitors would represent important tools for elucidating the therapeutic potential of this protein family. We recently reported the structure-based design of trisubstituted cyclopropane class IIa-selective HDAC inhibitors as potential therapeutics in HD. 6 This improved selectivity was driven by exploiting a selectivity pocket ( Figure 1, shown with compound 13) that is not present in the class I HDAC isoforms. This pocket is formed as a consequence of a tyrosine-histidine substitution. 7 We now report the discovery of tetrasubstituted cyclopropane hydroxamic acid class IIa HDAC inhibitors, with additional substitution at C1 (Figure 1). These compounds exhibited improved pharmacokinetic profiles, and so may provide a further means for evaluating efficacy in preclinical in vivo HD disease models.

Using an iterative structure−activity relationship driven approach, we identified a CNS-penetrant 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO, 12) with a pharmacokinetic profile suitable for probing class IIa histone deacetylase (HDAC) inhibition in vivo. Given the lack of understanding of endogenous class IIa HDAC substrates, we developed a surrogate readout to measure compound effects in vivo, by exploiting the >100-fold selectivity compound 12 exhibits over class I/IIb HDACs. We achieved adequate brain exposure with compound 12 in mice to estimate a class I/IIb deacetylation EC 50 , using class I substrate H4K12 acetylation and global acetylation levels as a pharmacodynamic readout. We observed excellent correlation between the compound 12 in vivo pharmacodynamic response and in vitro class I/IIb cellular activity. Applying the same relationship to class IIa HDAC inhibition, we estimated the compound 12 dose required to inhibit class IIa HDAC activity, for use in preclinical models of Huntington's disease.

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Cyclopentenyl allylic acetates have been prepared in diastereoisomerically enriched form by modification of the Prins reaction. Palladium(o) catalysed coupling between these allylic acetates and a heteroaromatic base provides a highly convergent and direct route for synthesising car bocycl i c 2',3' -d ide h y d ro -2',3'd ideoxy n ucleosides. The met hod is exem pl if ied by the c o u pl i ng reaction with adenine which yields ( & ) -2',3'-didehydro-2',3'-dideoxyaristeromycin 5'-O-acetate 22 in 50% yield. This has been converted in two steps into ( + ) -aristeromycin triacetate 5.Nucleosides exhibit a wide range of biological properties of both agrochemical and pharmaceutical interest.' Amongst the many structural types, carbocyclic nucleosides are of special interest, since they are not susceptible to degradation in viuo by nucleosidases and phosphorylases.2 For example carbovir 1 and its adenine analogue 2 exhibit antiviral a ~t i v i t y . ~ Current Paper 1 /03089B

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