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- W163148640 abstract "Glucokinase is an enzyme responsible for the conversion of glucose into glucose-6 phosphate and plays a central role as a glucose sensor in the regulation of glucose homeostasis. Accordingly, agents that cause activation of glucokinase have potential for the treatment of type 2 diabetes (T2D). Here we describe a summary of our optimisation of a series of glucokinase activators starting with a hit from high-throughput screening. This work culminated in the discovery of the Phase IIb clinical candidate AZD1656. Our account of the journey articulates the many medicinal chemistry challenges that the programme has overcome and covers challenges in potency, protein binding, off-target pharmacology leading to toxicological findings, solubility, permeability, crystallinity, hERG, Ames activity and absorption. In so doing, it highlights the use of quantitative lipophilicity–property relationships and thorough data analysis in guiding medicinal chemistry design, and also that adherence to defined optimal lipophilicity ranges can lead to improved chances of identifying compounds of superior overall technical profile." @default.
- W163148640 created "2016-06-24" @default.
- W163148640 creator A5047398290 @default.
- W163148640 creator A5063837282 @default.
- W163148640 date "2013-01-01" @default.
- W163148640 modified "2023-09-30" @default.
- W163148640 title "Property-Based Design in the Optimisation of Benzamide Glucokinase Activators" @default.
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- W163148640 doi "https://doi.org/10.1016/b978-0-444-62652-3.00001-6" @default.
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