Bioorganic & Medicinal Chemistry Letters 18 (2008) 3386–3391
The discovery of fused pyrrole carboxylic acids as novel, potent
D-amino acid oxidase (DAO) inhibitors
Tim Sparey,a,* Pravien Abeywickrema,d Sarah Almond,b Nick Brandon,b Noel Byrne,d
Alister Campbell,a Pete H. Hutson,b,c Marlene Jacobson,c Brian Jones,a Sanjeev Munshi,d
Danette Pascarella,c Andrew Pike,a G. Sridhar Prasad,d Nancy Sachs,c Melanie Sakatis,a
Vinod Sardana,d Shankar Venkatramane and Mary Beth Younge
aDepartment of Medicinal Chemistry, Merck Sharp & Dohme, The Neuroscience Research Centre, Terlings Park, Harlow,
Essex CM20 2QR, UK
bDepartment of Molecular & Cellular Neuroscience, Merck Sharp & Dohme, The Neuroscience Research Centre,
Terlings Park, Harlow, Essex CM20 2QR, UK
cDepartment of Schizophrenia Research, Merck & Co., Inc., Sumneytown Pike, West Point, PA, USA
dDepartment of Structural Biology, Merck & Co., Inc., Sumneytown Pike, West Point, PA, USA
eDepartment of Medicinal Chemistry, Merck & Co., Inc., Sumneytown Pike, West Point, PA, USA
Received 29 January 2008; revised 8 April 2008; accepted 10 April 2008
Available online 13 April 2008
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.
Ó 2008 Elsevier Ltd. All rights reserved.
Schizophrenia is a condition that affects up to 1% of the
population. Current therapies are inadequate and one
new approach is to address the ‘NMDA hypofunction’
hypothesis1 by developing drugs to enhance NMDA
receptor function, for example, elevation of brain gly-
cine through inhibition of the glycine transporter
(GLYT1).2
bit D-amino acid oxidase (DAO), the enzyme primarily
responsible for metabolising D-serine.4
A number of reports profile compounds including indole-
s,5a benzisoaxoles5b,c and pyrrole/pyrazole derivatives5c,d
with potent in vitro activity for DAO inhibition and ben-
efits in animal models of cognitive and positive symptoms
of schizophrenia. There are striking similarities between
these classes of compounds; they are all low molecular
weight, carboxylic acids.
An alternative approach is to increase the brain concen-
tration of D-serine, a co-agonist of the NMDA receptor,
and would therefore be expected to increase the activa-
tion of the NMDA receptor.
Described herein is our approach to the identification of
potent DAO inhibitors and follow-up studies utilising
X-ray crystallography to design analogues suitable for
in vivo profiling.
Clinical evidence to support this hypothesis is mixed,
but some benefit was seen in patients when D-serine
was used as an add-on to atypical anti-psychotics.3
One approach to increase brain D-serine levels is to inhi-
Keywords: Schizophrenia; D-Amino acid oxidase (DAO) inhibitor.
*
Corresponding author at present address: Merck Sharp & Dohme,
Licensing & External Research Europe, Hertford Road, Hoddesdon
EN11 9BU, UK. Tel.: +44 1992 452838; fax: +44 1992 441907; e-
Scheme 1. Reagents and condition: (a) EtO2CCH2N3, NaOEt, EtOH
(67%); (b) Toluene, reflux (77%); (c) NaOH (97%).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.04.020