Alzheimer's disease (AD) is a common and devastating neurodegenerative disorder for which no cure exists. AD often results in complete incapacitation, profound impairment of the quality of life, enormous burdens on family caregivers and society, and ultimately death from one of a variety of complications of the disease. In the US alone there are over 5 million people with AD and this figure is expected to grow to over 16 million by 2050 with costs exceeding $1.1 trillion. The cytokine transforming growth factor (TGF)-�1 is an organizer of the brain's response to injury and has been shown to have both immunomodulatory and neuroprotective effects in models of brain injury and degeneration. Since TGF-� receptor expression is reduced in human AD brains possibly leading to reduced signaling in the neurons as well. Increasing TGF-� signaling may reduce neurodegeneration and be beneficial for the treatment of individuals with mild to moderate AD. From a screening program to identify small molecules that mimic the beneficial effects of TGF-�, a hit, SRI-011273, was discovered. An optimization program was undertaken resulting in SRI-011381, a small molecule with promising in vitro and in vivo efficacy and safety data, which will be described.

Development of an agonist of the TGF-beta signaling pathway to treat Alzheimer's disease

248th National Meeting (2014)

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