Synthesis and chemical biology of ILS-920: A novel non-immunosuppressive rapamycin analog with efficacy in multiple animal models of ischemic stroke

ORGN 282

Edmund I. Graziani, graziaei@wyeth.com1, Benfang Ruan1, Shi Liang2, Danni Liu2, Flora Jow2, Mark Bowlby2, Yi Chen2, Mary Lynn Mercado2, Xidong Feng1, Leonard McDonald1, Margaret M. Zaleska2, Andrew Wood2, Peter Reinhart2, Menelas N. Pangalos2, Ronald L. Magolda1, Jerauld Skotnicki1, Frank E. Koehn, koehnf@wyeth.com1, Guy T. Carter, carterg@wyeth.com3, Magid Abou-Gharbia1, and Kevin Pong2. (1) Chemical & Screening Sciences, Wyeth Research, 401 N. Middletown Rd., Pearl River, NY 10965, (2) Discovery Neuroscience, Wyeth Research, CN8000, Princeton, NJ 08543-8000, (3) Wyeth Research, P.O. Box CN 8000, Princeton, NJ 08543
Rapamycin is an immunosuppressive immunophilin ligand reported as having neurotrophic activity. We show for the first time that modification of rapamycin at the mTOR binding region, to yield the novel immunophilin ligand ILS-920, generates a compound having potent neurotrophic activity in cortical neuronal cultures and greatly reduced immunosuppressive activity. Administration of ILS-920 significantly improved neurological deficits following permanent middle cerebral artery occlusion (pMCAO), even when dosed up to 24 hours post occlusion. Surprisingly, ILS-920 showed higher binding selectivity for FKBP52 versus FKBP12 than that of rapamycin, in contrast to previously reported immunophilin ligands. Affinity purification revealed two key binding proteins, the immunophilin FKBP52 and the ß1-subunit of L-type voltage dependent Ca2+ channels (CACNB1). These findings suggest that ILS-920 may be a novel therapeutic candidate, with a large therapeutic treatment window, in the treatment of stroke and stroke recovery.
 

Young Industrial Investigators
9:00 AM-12:05 PM, Monday, August 20, 2007 BCEC -- Ballroom, Oral

Division of Organic Chemistry

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