title: The discovery of fused pyrrole carboxylic acids as novel, potent D-amino acid oxidase (DAO) inhibitors.
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.
authors.affiliation: Department of Medicinal Chemistry, Merck Sharp & Dohme, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK. tim_sparey@merck.com
authors.forename: Tim
authors.initials: T
authors.lastname: Sparey
authors.forename: Pravien
authors.initials: P
authors.lastname: Abeywickrema
authors.forename: Sarah
authors.initials: S
authors.lastname: Almond
authors.forename: Nick
authors.initials: N
authors.lastname: Brandon
authors.forename: Noel
authors.initials: N
authors.lastname: Byrne
authors.forename: Alister
authors.initials: A
authors.lastname: Campbell
authors.forename: Pete H
authors.initials: PH
authors.lastname: Hutson
authors.forename: Marlene
authors.initials: M
authors.lastname: Jacobson
authors.forename: Brian
authors.initials: B
authors.lastname: Jones
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Munshi
authors.forename: Danette
authors.initials: D
authors.lastname: Pascarella
authors.forename: Andrew
authors.initials: A
authors.lastname: Pike
authors.forename: G Sridhar
authors.initials: GS
authors.lastname: Prasad
authors.forename: Nancy
authors.initials: N
authors.lastname: Sachs
authors.forename: Melanie
authors.initials: M
authors.lastname: Sakatis
authors.forename: Vinod
authors.initials: V
authors.lastname: Sardana
authors.forename: Shankar
authors.initials: S
authors.lastname: Venkatraman
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Young
mesh_terms: 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
chemical_list: D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D011758:Pyrroles; D012694:Serine; D003605:D-Amino-Acid Oxidase