Design and synthesis of boron-containing PDE4 inhibitors using soft-drug strategy for potential dermatologic anti-inflammatory application.
PDE4 inhibitors are a validated approach as anti-inflammatory agents but are limited by systemic side effects including emesis. We report a soft-drug strategy incorporating a carboxylic ester group into boron-containing PDE4 inhibitors leading to the discovery of a series of benzoxaborole compounds with good potency (for example IC(50)=47 nM of compound 2) and low emetic activity. These compounds are intended for dermatological use further limiting possible systemic side effects.
Zhang
Yong-Kang
YK
Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA. yzhang@anacor.com
Plattner
Jacob J
JJ
Akama
Tsutomu
T
Baker
Stephen J
SJ
Hernandez
Vincent S
VS
Sanders
Virginia
V
Freund
Yvonne
Y
Kimura
Richard
R
Bu
Wei
W
Hold
Karin M
KM
Lu
Xiao-Song
XS
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001895:Boron / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D004423:Ear / Q000473:pathology; D004487:Edema / Q000188:drug therapy; D006801:Humans; D051379:Mice; D058988:Phosphodiesterase 4 Inhibitors
D000893:Anti-Inflammatory Agents; D058988:Phosphodiesterase 4 Inhibitors; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D001895:Boron