In vitro pharmacological profiling of R406 identifies molecular targets underlying the clinical effects of fostamatinib.

Off-target pharmacology may contribute to both adverse and beneficial effects of a new drug. In vitro pharmacological profiling is often applied early in drug discovery; there are fewer reports addressing the relevance of broad profiles to clinical adverse effects. Here, we have characterized the pharmacological profile of the active metabolite of fostamatinib, R406, linking an understanding of drug selectivity to the increase in blood pressure observed in clinical studies.

Systematic exploration of dual-acting modulators from a combined medicinal chemistry and biology perspective.

The traditional drug discovery strategy of pursuing "one compound-one target" has had difficulties delivering novel therapies for complex diseases currently lacking adequate treatments. An alternative and complementary approach is the design of multitargeted modulators simultaneously addressing multiple pathological mechanisms or overcoming pathway robustness. In this study, we propose a methodology to increase the probability of success for developing dual-acting modulators by systematically and rationally evaluating all dual-acting modulator opportunities within a specific disease area.

Relationship of serum markers of cartilage metabolism to imaging and clinical outcome measures of knee joint structure.

Background: Biomarkers of cartilage metabolism have prognostic potential.

Objective: To examine whether serum cartilage biomarkers, cartilage oligomeric matrix protein (COMP), N-propeptide of type IIA procollagen (PIIANP), type II collagen breakdown product (collagen type-II cleavage (C2C)) predict cartilage volume loss and knee joint replacement.

Methods: 117 subjects with knee osteoarthritis (OA) had MRI at baseline and 2 years.