Discovery of a Potent and Orally Active Hedgehog Pathway Antagonist (IPI-926)

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• 作者：Martin R. Tremblay ; Andr Lescarbeau ; Michael J. Grogan ; Eddy Tan ; Grace Lin ; Brian C. Austad ; Lin-Chen Yu ; Mark L. Behnke ; Somarajan J. Nair ; Margit Hagel ; Kerry White ; James Conley ; Joseph D. Manna
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：July 23, 2009
• 年：2009
• 卷：52
• 期：14
• 页码：4400-4418
• 全文大小：1084K
• 年卷期：v.52,no.14(July 23, 2009)
• ISSN：1520-4804

文摘

Recent evidence suggests that blocking aberrant hedgehog pathway signaling may be a promising therapeutic strategy for the treatment of several types of cancer. Cyclopamine, a plant Veratrum alkaloid, is a natural product antagonist of the hedgehog pathway. In a previous report, a seven-membered D-ring semisynthetic analogue of cyclopamine, IPI-269609 (2), was shown to have greater acid stability and better aqueous solubility compared to cyclopamine. Further modifications of the A-ring system generated three series of analogues with improved potency and/or solubility. Lead compounds from each series were characterized in vitro and evaluated in vivo for biological activity and pharmacokinetic properties. These studies led to the discovery of IPI-926 (compound 28), a novel semisynthetic cyclopamine analogue with substantially improved pharmaceutical properties and potency and a favorable pharmacokinetic profile relative to cyclopamine and compound 2. As a result, complete tumor regression was observed in a Hh-dependent medulloblastoma allograft model after daily oral administration of 40 mg/kg of compound 28.