The discovery of fused pyrrole carboxylic acids as novel, potent D-amino acid oxidase (DAO) inhibitors

  • Bioorg Med Chem Lett. 2008 Jun 1;18(11):3386-91. doi: 10.1016/j.bmcl.2008.04.020.
Tim Sparey  1 ,  Pravien Abeywickrema ,  Sarah Almond ,  Nick Brandon ,  Noel Byrne ,  Alister Campbell ,  Pete H Hutson ,  Marlene Jacobson ,  Brian Jones ,  Sanjeev Munshi ,  Danette Pascarella ,  Andrew Pike ,  G Sridhar Prasad ,  Nancy Sachs ,  Melanie Sakatis ,  Vinod Sardana ,  Shankar Venkatraman ,  Mary Beth Young
Affiliations
  • 1. Department of Medicinal Chemistry, Merck Sharp & Dohme, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK. [email protected]
PMID: 18455394 DOI: 10.1016/j.bmcl.2008.04.020
Abstract

The 'NMDA hypofunction hypothesis of schizophrenia' can be tested in a number of ways. DAO is the enzyme primarily responsible for the metabolism of d-serine, a co-agonist for the NMDA Receptor. We identified novel DAO inhibitors, in particular, acid 1, which demonstrated moderate potency for DAO in vitro and ex vivo, and raised plasma d-serine levels after dosing IP to rats. In parallel, analogues were prepared to survey the SARs of 1.

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