title: 8-Substituted analogues of 3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-adenine: highly potent and selective PDE4 inhibitors.
abstract: 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.
authors.affiliation: Purdue Pharma LP, 6 Cedar Brook Drive, Cranbury, New Jersey 08512, USA. john.whitehead@pharma.com
authors.forename: John W F
authors.initials: JW
authors.lastname: Whitehead
authors.forename: Gary P
authors.initials: GP
authors.lastname: Lee
authors.forename: Parviz
authors.initials: P
authors.lastname: Gharagozloo
authors.forename: Peter
authors.initials: P
authors.lastname: Hofer
authors.forename: André
authors.initials: A
authors.lastname: Gehrig
authors.forename: Peter
authors.initials: P
authors.lastname: Wintergerst
authors.forename: Donald
authors.initials: D
authors.lastname: Smyth
authors.forename: William
authors.initials: W
authors.lastname: McCoull
authors.forename: Mohamed
authors.initials: M
authors.lastname: Hachicha
authors.forename: Aniket
authors.initials: A
authors.lastname: Patel
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Kyle
mesh_terms: 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
chemical_list: D007527:Isoenzymes; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human; D000225:Adenine