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An octahydro-cyclopenta[c]pyrrole series of inhibitors of the type 1 glycine transporter.
Bioorganic & medicinal chemistry letters 2009 Dec 23; In press
Lowe J JA, Deninno S SL, Drozda S SE, Schmidt C CJ, Ward K KM, David Tingley F, Sanner M, Tunucci D, Valentine J
Pfizer Global Research & Development, Eastern Point Road, Groton CT 06340, United States.
We describe a novel series of inhibitors of the type 1 glycine transporter (GlyT1) as an approach to relieving the glutamatergic deficit that is thought to underlie schizophrenia. Synthesis and SAR follow-up of a series of octahydro-cyclopenta[c]pyrrole derivatives afforded potent in vitro inhibition of GlyT1 as well as in vivo activity in elevating CSF glycine. We also found that a 3-O(c-pentyl), 4-F substituent may serve as a surrogate for the widely used 3-trifluoromethoxy group, suggesting its application as an isostere for future medicinal chemistry studies.
Keywords: type 1 glycine transporter schizophrenia