2. Academic Validation
  3. Semisynthetic cyclopamine analogues as potent and orally bioavailable hedgehog pathway antagonists

Semisynthetic cyclopamine analogues as potent and orally bioavailable hedgehog pathway antagonists

  • J Med Chem. 2008 Nov 13;51(21):6646-9. doi: 10.1021/jm8008508.
Martin R Tremblay 1,  Marta Nevalainen,  Somarajan J Nair,  James R Porter,  Alfredo C Castro,  Mark L Behnke,  Lin-Chen Yu,  Margit Hagel,  Kerry White,  Kerrie Faia,  Louis Grenier,  Matthew J Campbell,  Jill Cushing,  Caroline N Woodward,  Jennifer Hoyt,  Michael A Foley,  Margaret A Read,  Jens R Sydor,  Jeffrey K Tong,  Vito J Palombella,  Karen McGovern,  Julian Adams
Affiliations

Affiliation

  • 1 Infinity Pharmaceuticals, Inc., 780 Memorial Drive, Cambridge, Massachusetts 02139, USA. Martin.Tremblay@infi.com
PMID: 18842035 DOI: 10.1021/jm8008508
Abstract

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.

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