The discovery of fused pyrrole carboxylic acids as novel, potent D-amino acid oxidase (DAO) inhibitors.
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.
Sparey
Tim
T
Department of Medicinal Chemistry, Merck Sharp & Dohme, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK. tim_sparey@merck.com
Abeywickrema
Pravien
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Almond
Sarah
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Brandon
Nick
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Byrne
Noel
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Campbell
Alister
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Hutson
Pete H
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Jacobson
Marlene
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Jones
Brian
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Munshi
Sanjeev
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Pascarella
Danette
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Pike
Andrew
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Prasad
G Sridhar
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Sachs
Nancy
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Sakatis
Melanie
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Sardana
Vinod
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Venkatraman
Shankar
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Young
Mary Beth
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D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012559:Schizophrenia / Q000188:drug therapy; D012694:Serine / Q000032:analysis / Q000097:blood
D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D011758:Pyrroles; D012694:Serine; D003605:D-Amino-Acid Oxidase