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Discovery of NVP-LDE225, a potent and selective biphenyl-3-carboxamide smoothened antagonist.

Pan, Shifeng and Wu, Xu and Jiang, Jiqing and Gao, Wenqi and Wan, Yongqin and Cheng, Dai and Han, Dong and Englund, Nathan and Wang, Yan and Peukert, Stefan and Miller-Moslin, Karen and Williams, Juliet and Yuan, Jing and Guo, Ribo and Vattay, Anthony and Jiang, Yun and Tsao, Jeffrey and Buonamici, Silvia and Sun, Fangxian and Pferdekamper, AnneMarie and Dodd, Stephanie and Tuntland, Tove and Maniara, Wieslawa and Kelleher Iii, Joseph and Warmuth, Markus and Dorsch, Marion (2010) Discovery of NVP-LDE225, a potent and selective biphenyl-3-carboxamide smoothened antagonist. ACS Medicinal Chemistry Letters, 1 (3). pp. 130-134. ISSN 1948-5875

Abstract

Blockade of aberrant hedgehog (Hh) signaling has shown promise for therapeutic intervention in cancer. A cell-based phenotypic high throughput screen was performed, and lead structure (1) was identified as an inhibitor of the Hh pathway via antagonism of the Smoothened receptor (Smo). Structure-activity relationship studies led to the discovery of a potent and specific Smoothened antagonist N-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)biphenyl-3-carboxamide (5m, NVP-LDE225) which is currently in clinical development.

Item Type: Article
Additional Information: archiving not formally supported by this publisher
Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2374

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