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: John W F Whitehead, Gary P Lee, Parviz Gharagozloo, Peter Hofer, André Gehrig, Peter Wintergerst, Donald Smyth, William McCoull, Mohamed Hachicha, Aniket Patel, Donald J Kyle
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 48 Issue 4 Pg. 1237-43 (Feb 24 2005) ISSN: 0022-2623 [Print] United States
• PMID: 15715490 (Publication Type: Journal Article)

Chemical References

• Isoenzymes
• 3',5'-Cyclic-AMP Phosphodiesterases
• Cyclic Nucleotide Phosphodiesterases, Type 4
• PDE4B protein, human
• Adenine

Topics

• 3',5'-Cyclic-AMP Phosphodiesterases (antagonists & inhibitors, chemistry)
• Adenine (analogs & derivatives, chemical synthesis, chemistry)
• Cyclic Nucleotide Phosphodiesterases, Type 4
• Humans
• Isoenzymes (antagonists & inhibitors, chemistry)
• Structure-Activity Relationship