8-Substituted analogues of 3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-adenine: highly potent and selective PDE4 inhibitors.
3-(3-Cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-adenine V11294 (1) has been identified as a lead structure, which selectively inhibits human lung PDE4 (436 nM) and is also active in a number of in vitro and in vivo models of inflammation. Here we describe the synthesis and pharmacology of a series of highly potent 8-[(benzyloxy)methyl]-substituted analogues, with potencies in the range 10-300 nM. In addition, several compounds showed interesting PDE4 subtype specificities, for example, the 3-thienyl derivative 5v, which showed 6-10 nM potency at PDE4B, D3, and D5 and a 20- to 200-fold selectivity over A and D2, respectively.
Whitehead
John W F
JW
Purdue Pharma LP, 6 Cedar Brook Drive, Cranbury, New Jersey 08512, USA. john.whitehead@pharma.com
Lee
Gary P
GP
Gharagozloo
Parviz
P
Hofer
Peter
P
Gehrig
André
A
Wintergerst
Peter
P
Smyth
Donald
D
McCoull
William
W
Hachicha
Mohamed
M
Patel
Aniket
A
Kyle
Donald J
DJ
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship
D007527:Isoenzymes; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human; D000225:Adenine