Neurodegenerative diseases are a major health problem particularly among the elderly. Drugs to prevent or slow down the death of neurons are urgently needed but are currently unavailable. We previously reported that the c-Raf inhibitor, GW5074 {5-iodo-3-[(3′,5′-dibromo-4′-hydroxyphenyl) methylene]-2-indolinone}, is protective in tissue culture and in vivo paradigms of neurodegeneration. However, at doses slightly higher than those at which it is protective, GW5074 displays toxicity when tested in neuronal cultures. We report herein the synthesis, biological evaluation, and structure-activity relationship (SAR) studies of novel 3-substituted indolin-2-one compounds that are highly neuroprotective but lack the toxicity of GW5074. Of the 45 analogs tested in this study, compounds 7, 37, 39, and 45 were found to be the most potent neuroprotective and thus represent promising lead compounds for preclinical development for the treatment of neurodegenerative disorders.

Objectives: Avascular necrosis (AVN) is associated with significant morbidity potentially causing severe pain and disability; patients with inflammatory bowel disease (IBD) have a higher prevalence of AVN compared with non-IBD populations. The purpose of our study was to determine the prevalence of AVN in our IBD population and to evaluate these subjects for the presence of clinical characteristics associated with AVN on computed tomography (CT) imaging. Methods: In 1313 IBD patients with abdomen/pelvis CT scans, we identified 27 patients (2.1%) with CT findings consistent with AVN. Through historical chart review, we confirmed that most patients had prior exposure to steroids, although 2 patients had no documented steroid exposure at all. Results: We found that 59% of the concurrent radiology reports did not comment on the presence of AVN, suggesting that incidental CT findings of AVN among IBD patients are likely underreported. Notably, we found that 63% of these cases had documented complaints of low-back and/or hip pain. Using logistic regression, we found an association between anti–neutrophil cytoplasmic antibody–positive status across IBD (p = 0.007) and a smoking history in Crohn disease (p = 0.03) with the presence of AVN. Conclusions: We found that a significant proportion of IBD patients with AVN are reported in their records as having hip or low-back pain, and review of CT imaging under dedicated bone windows may identify AVN among this population. Our findings also suggest that additional etiological factors, beyond corticosteroids, contribute to the development of AVN in IBD. Further investigation is warranted regarding the mechanisms associated with AVN in IBD.