Inhibition of cyclic nucleotide phosphodiesterase by derivatives of 1,3-bis(cyclopropylmethyl)xanthine.
Alkylation of the selective type IV phosphodiesterase inhibitor, 8-amino-1,3-bis(cyclopropylmethyl)-xanthine (1, BRL 61063), led exclusively to the N-7 substituted derivatives 2-9, which showed varying selectivities for the PDE type IV isoenzyme relative to PDE Va. The 4-methoxybenzyl derivative 6 in particular was a highly potent PDE Va inhibitor (IC50 0.14 microM) and showed a 24-fold selectivity for this isoenzyme relative to PDE IV. Sulfonation of 1 was more complex, with the product profile being highly dependent on the reaction conditions. As with alkylation, sulfonation at N-7 generally increased potency against PDE Va, especially in the aryl-containing moieties lacking strongly electron-withdrawing substituents (12, 15-17, 19). Bis-arylsulfonation at the exocyclic amino group generally reduced inhibitory potency against both PDE IV and Va. An 8-amidino compound 33, formed by the unusual reaction of 1 with N-methylpyrrolidinone in the presence of benzenesulfonyl chloride, had an IC50 value of 0.05 microM against PDE Va and is believed to be the most potent inhibitor of this isoenzyme reported. No correlation of PDE IV inhibition with displacement of [3H]rolipram from its high-affinity binding site was demonstrated. This suggests that either the catalytic site and the rolipram binding site are not the same or that PDE IV can exist in two conformations, only one of which binds to rolipram with high affinity, and that the compounds described vary in their selectivity for this isoform.
Buckle
D R
DR
SmithKline Beecham Pharmaceuticals, Epsom, Surrey, U.K.
Arch
J R
JR
Connolly
B J
BJ
Fenwick
A E
AE
Foster
K A
KA
Murray
K J
KJ
Readshaw
S A
SA
Smallridge
M
M
Smith
D G
DG
D000241:Adenosine / Q000037:antagonists & inhibitors; D000478:Alkylation; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011760:Pyrrolidinones / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D014970:Xanthines; C086163:8-amino-1,3-bis(cyclopropylmethyl)xanthine; D010727:Phosphoric Diester Hydrolases; D020889:Rolipram; D000241:Adenosine