Bioorg Med Chem Lett. 2010 Feb 1;20(3):907-11. Epub 2009 Dec 23.

An octahydro-cyclopenta[c]pyrrole series of inhibitors of the type 1 glycine transporter.

Lowe JA 3rd, Deninno SL, Drozda SE, Schmidt CJ, Ward KM, David Tingley F 3rd, Sanner M, Tunucci D, Valentine J.

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Pfizer Global Research & Development, Eastern Point Road, Groton CT 06340, United States.

Abstract

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.

PMID:: 20045321; [PubMed - indexed for MEDLINE]

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