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Structure-efficiency relationship of [1,2,4]triazol-3-ylamines as novel nicotinamide isosteres that inhibit tankyrases

Majumdar, Dyuti and Chin, Donovan and Fortin, Pascal and Feng, Yun and Gould, Ty and Kirby, Christina and Shao, Wenlin and Stams, Travis and Waters, Nigel and Shultz, Michael (2013) Structure-efficiency relationship of [1,2,4]triazol-3-ylamines as novel nicotinamide isosteres that inhibit tankyrases. Journal of Medicinal Chemistry, 56 (17). pp. 7049-7059. ISSN 0022-2623

Abstract

Tankyrases 1 and 2 are members of the poly(ADP-ribose) polymerase (PARP) family of enzymes that modulate Wnt pathway signaling. While amide- and lactam-based nicotinamide mimetics that inhibit tankyrase activity, such as XAV939, are well-known, herein we report the discovery and evaluation of a novel nicotinamide isostere that demonstrates selectivity over other PARP family members. We demonstrate the utilization of lipophilic efficiency-based structure-efficiency relationships (SER) to rapidly drive the evaluation of this series. These efforts led to a series of selective, cell-active compounds with solubility, physicochemical, and in vitro properties suitable for further optimization. © 2013 American Chemical Society.

Item Type: Article
Date Deposited: 25 Nov 2017 00:45
Last Modified: 25 Jan 2019 00:46
URI: https://oak.novartis.com/id/eprint/9678

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