Kim Louise Hirst

Discovery of a series of imidazopyrazine small molecule inhibitors of the kinase MAPKAPK5, that show activity using in vitro and in vivo models of rheumatoid arthritis

MAPKAPK5 has been proposed to play a role in regulation of matrix metalloprotease expression and so to be a potential target for intervention in rheumatoid arthritis. We present here the identification of a series of compounds against this target which are effective in both biochemical and cell assays. The expansion of the series is described, along with early SAR and pharmacokinetics for some representative compounds.

A NOVEL GABAAA5 NEGATIVE ALLOSTERIC MODULATOR ENHANCES LONG-TERM POTENTIATION AND IMPROVES COGNITION IN PRECLINICAL MODELS

age, education level, and gender. There was a significant e4 x age interaction (p1⁄40.03). We found no associations between e4+ and processing speed or attention, or between family history of e4+ and cognitive test scores. There were significant associations between self-reported memory problems and both e4+ (p<0.001) and family history of e4+ (p<0.001). We identified 2032 “likely prodromal” and 6227 “likely preclinical” participants for AD trials. Of those likely eligible participants who reported their e4 genotype (n1⁄41650), 16% of prodromal and 4% of preclinical were e4+. Conclusions: In a large, novel, internet-based cohort, self-reported e4 is associated with online memory test scores in younger participants, and cognitively-normal participants. In the general cohort, age eclipses the effects of e4 genotype on memory scores. Self-reportedmemory problems are strongly associated with e4 evenwhen controlling for other variables. BHR participants identified as likely prodromal have four times greater prevalence of e4+ than older adults with normal cognitive test scores. Self-report of e4 in BHR can be used to prescreen for AD trials requiring e4, facilitate AD trials, and accelerate development of new AD treatments.