Semisynthetic cyclopamine analogues as potent and orally bioavailable hedgehog pathway antagonists
MR Tremblay, M Nevalainen, SJ Nair… - Journal of medicinal …, 2008 - ACS Publications
MR Tremblay, M Nevalainen, SJ Nair, JR Porter, AC Castro, ML Behnke, LC Yu, M Hagel…
Journal of medicinal chemistry, 2008•ACS PublicationsHerein is reported the synthesis of a novel class of hedgehog antagonists derived from
cyclopamine. The acid sensitive D-ring of cyclopamine was homologated utilizing a
sequence of chemoselective cyclopropanation and stereoselective acid-catalyzed
rearrangement. Further modification of the A/B-ring homoallylic alcohol to the conjugated
ketone led to the discovery of new cyclopamine analogues with improved pharmaceutical
properties and in vitro potency (EC50) ranging from 10 to 1000 nM.
cyclopamine. The acid sensitive D-ring of cyclopamine was homologated utilizing a
sequence of chemoselective cyclopropanation and stereoselective acid-catalyzed
rearrangement. Further modification of the A/B-ring homoallylic alcohol to the conjugated
ketone led to the discovery of new cyclopamine analogues with improved pharmaceutical
properties and in vitro potency (EC50) ranging from 10 to 1000 nM.
Herein is reported the synthesis of a novel class of hedgehog antagonists derived from cyclopamine. The acid sensitive D-ring of cyclopamine was homologated utilizing a sequence of chemoselective cyclopropanation and stereoselective acid-catalyzed rearrangement. Further modification of the A/B-ring homoallylic alcohol to the conjugated ketone led to the discovery of new cyclopamine analogues with improved pharmaceutical properties and in vitro potency (EC50) ranging from 10 to 1000 nM.
ACS Publications