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Inhibition of Type 4 Cyclic Nucleotide Phosphodiesterase by 8‐Chloroxanthines
Author(s) -
Arch Jonathan R. S.,
Buckle Derek R.,
Connolly Brendan J.,
Faller Andrew,
Fenwick Ashley E.,
Murray Kenneth J.,
Rami Harshad K.,
Smallridge Mark S.,
Smith David G.
Publication year - 1996
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.19963290406
Subject(s) - chemistry , phosphodiesterase , isozyme , bromine , substituent , selectivity , cyclic nucleotide phosphodiesterase , nucleotide , stereochemistry , chlorine , xanthine , cyclic nucleotide , enzyme , structure–activity relationship , biochemistry , in vitro , organic chemistry , gene , catalysis
In an endeavour to develop isoenzyme selective inhibitors of the cyclic nucleotide phosphodiesterases, structural modifications of 8‐amino‐1,3‐bis(cyclopropylmethyl)xanthine (BRL 61063) have been investigated. Particularly significant was the observation that certain 7‐aralkyl derivatives incorporating chlorine or bromine in place of the 8‐amino substituent afforded selective inhibitors of the PDE 4 isoenzyme. The 7‐(2‐naphthylmethyl) derivatives of 8‐chloroxanthine 16 and 8‐bromoxanthine 17 in particular showed sub‐micromolar IC 50 values against PDE 4 while eliciting some 10 and 100‐fold or greater selectivity, respectively, against the 1b, 1c, 2, 3, and 5a isoenzymes.