Semisynthetic cyclopamine analogues as potent and orally bioavailable hedgehog pathway antagonists.
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 (EC 50) ranging from 10 to 1000 nM.
Tremblay
Martin R
MR
Infinity Pharmaceuticals, Inc., 780 Memorial Drive, Cambridge, Massachusetts 02139, USA. Martin.Tremblay@infi.com
Nevalainen
Marta
M
Nair
Somarajan J
SJ
Porter
James R
JR
Castro
Alfredo C
AC
Behnke
Mark L
ML
Yu
Lin-Chen
LC
Hagel
Margit
M
White
Kerry
K
Faia
Kerrie
K
Grenier
Louis
L
Campbell
Matthew J
MJ
Cushing
Jill
J
Woodward
Caroline N
CN
Hoyt
Jennifer
J
Foley
Michael A
MA
Read
Margaret A
MA
Sydor
Jens R
JR
Tong
Jeffrey K
JK
Palombella
Vito J
VJ
McGovern
Karen
K
Adams
Julian
J
D000284:Administration, Oral; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015394:Molecular Structure; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014704:Veratrum Alkaloids / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry
D053823:Hedgehog Proteins; D014704:Veratrum Alkaloids; C000541:cyclopamine