Bioorganic & Medicinal Chemistry Letters
D-Amino acid oxidase inhibitors based on the
-hydroxy-1,2,4-triazin-6(1H)-one scaffold
5
Niyada Hin , Bridget Duvall , James F. Berry , Dana V. Ferraris a,c, Rana Rais a,b, Jesse Alt a,
a
a
a,b
a,d
a,b
a,b,
⇑
Camilo Rojas , Barbara S. Slusher , Takashi Tsukamoto
a
Johns Hopkins Drug Discovery Program, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA
Department of Neurology, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA
Department of Chemistry, McDaniel College, 2 College Hill, Westminster, MD 21157, USA
b
c
d
Department of Molecular and Comparative Pathobiology, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 3-substituted 5-hydroxy-1,2,4-triazin-6(1H)-one derivatives were designed and synthesized
Received 23 December 2015
Revised 19 February 2016
Accepted 22 February 2016
Available online xxxx
as a new class of D-amino acid oxidase (DAAO) inhibitors. Some of the newly synthesized derivatives
showed potent inhibitory activity against human DAAO with IC50 values in the nanomolar range.
Among them, 6-hydroxy-3-phenethyl-1,2,4-triazin-5(2H)-one 6b and 3-((6-fluoronaphthalen-2-yl)
methylthio)-6-hydroxy-1,2,4-triazin-5(2H)-one 6m were found to be metabolically stable in mouse liver
microsomes. In addition, compound 6b was found to be orally available in mice and able to enhance
Keywords:
plasma
D-serine levels following its co-administration with
D
-serine compared to the oral administration
D-Amino acid oxidase
of D-serine alone.
Flavoenzyme
Pharmacokinetics
Schizophrenia
Ó 2016 Elsevier Ltd. All rights reserved.
D-Serine
D
-Amino acid oxidase (DAAO, EC 1.4.3.3) catalyzes the oxidative
binding site.6 2-Substituted 6-hydroxy-1,2,4-triazine-3,5(2H,4H)-
diones such as 3 exhibited not only potent DAAO inhibitory activity
but also improved metabolic stability compared to 1–2 in liver
deamination of neutral -amino acids including -serine, a co-agonist
D
D
at the glycine modulatory site of NMDA receptors. Because of the
implication that hypofunction of NMDA receptors plays an
important role in the pathophysiology of schizophrenia, there has
been considerable efforts in developing DAAO inhibitors as a phar-
7
microsomes. This secondary binding site was also exploited by
8
9
carboxylate-based DAAO inhibitors such as 4 and 5. In the search
for a new class of DAAO inhibitors, we have examined a variety of
scaffolds that may serve as a bioisostere for the carboxylic acid
moiety interacting with the active site of DAAO.
macological approach for increasing
D-serine and facilitating
NMDA receptor-mediated neurotransmission. DAAO has been also
implicated as a potential therapeutic target for the treatment of
chronic pain since hydrogen peroxide, a reactive oxygen species
co-generated by DAAO, is believed to contribute to pain hypersen-
We found that the 5-hydroxy-1,2,4-triazin-6(1H)-one moiety
can serve as an effective carboxylate isostere and that its 3-posi-
tion can be utilized to attach a branched chain that extends into
the secondary binding site of DAAO. These derivatives of 6 were
found to potently inhibit human DAAO with IC50 values in the
nanomolar range. In this Letter, we describe the SAR for this new
class of DAAO inhibitors as well as the pharmacological properties
of selected compounds, including metabolic stability, oral
1
sitivity. In the past decade, a wide variety of DAAO inhibitors have
been identified by several research groups.2 As shown in Figure 1,
newer scaffolds of DAAO inhibitors contain a branched chain,
which occupies the secondary pocket adjacent to the active site
of DAAO recognized by the crystal structure of human DAAO in
,3
4
complex with imino-DOPA. For example, our group exploited this
secondary binding site using kojic acid derivatives represented by
compound 1. Similarly, a group at Astellas reported potent DAAO
inhibitors including 2a–b based on a 4-hydroxypyridazin-3(2H)-
pharmacokinetics, and effects on plasma levels of
following oral co-administration.
D-serine in mice
5
Synthetic methods of 3-substituted 5-hydroxy-1,2,4-triazin-6
(1H)-one derivatives 6a–o are illustrated in Scheme 1. 3-Arylalkyl
derivatives 6a–c were prepared by first treating nitriles 7a–c with
hydrogen chloride gas to form the corresponding acetimidate
one scaffold with a phenethyl group extending to the secondary
1
0
⇑
8a–c. Subsequent reaction with methyl chlorooxoacetate in the
presence of DIEA, followed by treatment with hydrazine afforded
960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
0