Novel derivatives of the steroid DHEA 1, a known uncompetitive inhibitor of G6PD, were designed, synthesized, and tested for their ability to inhibit this dehydrogenase enzyme. Several compounds with approximately 10-fold improved potency in an enzyme assay were identified, and this improved activity translated to efficacy in a cellular assay. The SAR for steroid inhibition of G6PD has been substantially developed; the 3β-alcohol can be replaced with 3β-H-bond donors such as sulfamide, sulfonamide, urea, and carbamate. Improved potency was achieved by replacing the androstane nucleus with a pregnane nucleus, provided a ketone at C-20 is present. For pregnan-20-ones incorporation of a 21-hydroxyl group is often beneficial. The novel compounds generally have good physicochemical properties and satisfactory in vitro DMPK parameters. These derivatives may be useful for examining the role of G6PD inhibition in cells and will assist the future design of more potent steroid inhibitors with potential therapeutic utility.
Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clinically approved multi-kinase inhibitors that target RET as a secondary pharmacology but additional activities, most notably inhibition of KDR, lead to dose-limiting toxicities. There is, therefore, a clinical need for more specific RET kinase inhibitors. Herein we report our efforts towards identifying a potent and selective RET inhibitor using vandetanib 1 as the starting point for structure-based drug design. Phenolic anilinoquinazolines exemplified by 6 showed improved affinities towards RET but, unsurprisingly, suffered from high metabolic clearance. Efforts to mitigate the metabolic liability of the phenol led to the discovery that a flanking substituent not only improved the hepatocyte stability, but could also impart a significant gain in selectivity. This culminated in the identification of 36; a potent RET inhibitor with much improved selectivity against KDR.
Starting from an HTS derived hit 1, application of biostructural data facilitated rapid optimization to lead 22, a novel AMPA receptor modulator. This is the first demonstration of how structure based drug design can be exploited in an optimization program for a glutamate receptor.
Starting from compound 1, we utilized biostructural data to successfully evolve an existing series into a new chemotype with a promising overall profile, exemplified by 19.
An experienced user of the Twiddler, a one-handed chording keyboard, averages speeds of 60 words per minute with letter-by-letter typing of standard test phrases. This fast typing rate coupled with the Twiddler's 3x4 button design, similar to that of a standard mobile telephone, makes it a potential alternative to multi-tap for text entry on mobile phones. Despite this similarity, there is very little data on the Twiddler's performance and learnability. We present a longitudinal study of novice users' learning rates on the Twiddler. Ten participants typed for 20 sessions using two different methods. Each session is composed of 20 minutes of typing with multi-tap and 20 minutes of one-handed chording on the Twiddler. We found that users initially have a faster average typing rate with multi-tap; however, after four sessions the difference becomes negligible, and by the eighth session participants type faster with chording on the Twiddler. Furthermore, after 20 sessions typing rates for the Twiddler are still increasing.Many wearable computer users [7,17] type with the HandyKey Twiddler ( Figure 1). This is a mobile one-handed chording keyboard with a keypad similar to a mobile phone. It has twelve keys arranged in a grid of three columns and four rows CHI 2004 | Paper
Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity.
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