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.
Infinity Pharmaceuticals, Inc., 780 Memorial Drive, Cambridge, Massachusetts 02139, USA. Martin.Tremblay@infi.com
Martin R
MR
Tremblay
Marta
M
Nevalainen
Somarajan J
SJ
Nair
James R
JR
Porter
Alfredo C
AC
Castro
Mark L
ML
Behnke
Lin-Chen
LC
Yu
Margit
M
Hagel
Kerry
K
White
Kerrie
K
Faia
Louis
L
Grenier
Matthew J
MJ
Campbell
Jill
J
Cushing
Caroline N
CN
Woodward
Jennifer
J
Hoyt
Michael A
MA
Foley
Margaret A
MA
Read
Jens R
JR
Sydor
Jeffrey K
JK
Tong
Vito J
VJ
Palombella
Karen
K
McGovern
Julian
J
Adams
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