Synthesis and structure-activity relationships of novel, potent mixed lineage kinase (MLK) inhibitors for Alzheimer's disease

MEDI 292

Ming Tao, mtao@cephalon.com1, Chung Ho Park, Reddeppareddy Dandu, dreddy@cephalon.com1, Allison Zulli1, Kurt Josef1, James L. Diebold1, Diane E. Gingrich1, Matthew Curry, mcurry@cephalon.com1, Jean Husten2, George Gessmen2, Thelma Angeles2, and Robert L. Hudkins, rhudkins@cephalon.com1. (1) Department of Medicinal Chemistry, Cephalon, Inc, 145 Brandywine Parkway, West Chester, PA 19380, (2) Department of Biochemistry, Cephalon, Inc, 145 Brandywine Parkway, West Chester, PA 19380
The c-Jun amino-terminal kinase (JNK) signaling pathway leads to activation of transcription factor and proapoptotic genes. The cascade plays an important role in neuronal apoptosis and may contribute to the neuronal loss associated with Alzheimer's disease and Parkinson's disease. The JNKs are stress activated protein kinases and are activated by the dual specificity MAP kinases MKK4 and MKK7, which are activated by upstream signals including the mixed lineage kinases (MLKs). The first generation compound from our program, CEP-1347, is a semi synthetic derivative of the indolocarbazole K-252a. CEP-1347, a potent inhibitor of the MLKs, displays a broad neuroprotective profile. In the search for potent synthetic MLK inhibitors, we identified dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole core 1 as novel MLK1/3 selective inhibitors. Toward our objective to further improve the MLK potency and bring DLK activity into the core, we prepared F-ring dihydroindazole analogs 2. The synthesis and SAR of this new dihydroindazole scafford will be discussed.

 

Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007