A new amino-masking group capable of pH-triggered amino-drug release

The prodrug approach is potentially useful for mitigating pharmaceutical problems-such as poor membrane permeability or stability-which commonly occur with amino drugs. On the other hand there persists a dearth of useful systems for masking amines that satisfy the prodrug requirements of good in vitro stability coupled with predictable and rapid drug release in response to a local tissue condition. This study describes an evaluation of aminoindanes as bioreversibly masked amines poised to undergo elimination to the parent amine. Several model amine and amino drug indanone derivatives were synthesised. pKa values were determined by capillary electrophoresis and pH rate profiles for elimination and amine liberation were measured. The aminoindanone system appears to have particular applicability to secondary amino substrates whose indanone derivatives are stable at low pH but undergo drug release at rates corresponding to first-order half-lives of <5 min at pH 7.4.