Maximizing diversity from a kinase screen: identification of novel and selective pan-Trk inhibitors for chronic pain.

We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.

To eat or not to eat red meat. A closer look at the relationship between restrained eating and vegetarianism in college females.

Previous research has suggested that vegetarianism may serve as a mask for restrained eating. The purpose of this study was to compare the dietary habits and lifestyle behaviors of vegetarians (n=55), pesco-vegetarians (n=28), semi-vegetarians (n=29), and flexitarians (n=37), to omnivores (n=91), who do not restrict animal products from their diets. A convenience sample of college-age females completed questionnaires about their eating habits, food choice motivations, and personality characteristics. Results indicated that while vegetarians and pesco-vegetarians were more open to new experiences and less food neophobic, they were not more restrained than omnivores. Rather semi-vegetarians; those who restricted only red meat from their diet, and flexitarians; those who occasionally eat red meat, were significantly more restrained than omnivores. Whereas food choices of semi-vegetarians and flexitarians were motivated by weight control, vegetarians and pesco-vegetarians' food choices were motivated by ethical concerns. By focusing specifically on semi-vegetarian and flexitarian subgroups, more effective approaches can be developed to ensure that their concerns about weight loss do not lead to unhealthful or disordered eating patterns.

Discovery of triarylethanolamine inhibitors of the Kv1.5 potassium channel.

A series of triarylethanolamine inhibitors of the Kv1.5 potassium channel have been prepared and evaluated for their effects in vitro and in vivo. The structure-activity relationship (SAR) studies described herein led to the development of potent, selective and orally active inhibitors of Kv1.5.