D-Amino acid oxidase inhibitors based on the 5-hydroxy-1,2,4-triazin-6(1H)-one scaffold

Niyada Hin; Bridget Duvall; James F Berry; Dana V Ferraris; Rana Rais; Jesse Alt; Camilo Rojas; Barbara S Slusher; Takashi Tsukamoto

doi:10.1016/j.bmcl.2016.02.068

D-Amino acid oxidase inhibitors based on the 5-hydroxy-1,2,4-triazin-6(1H)-one scaffold

Bioorg Med Chem Lett. 2016 Apr 15;26(8):2088-91. doi: 10.1016/j.bmcl.2016.02.068. Epub 2016 Feb 23.

Authors

Niyada Hin¹, Bridget Duvall¹, James F Berry², Dana V Ferraris³, Rana Rais², Jesse Alt¹, Camilo Rojas⁴, Barbara S Slusher², Takashi Tsukamoto⁵

Affiliations

¹ Johns Hopkins Drug Discovery Program, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA.
² 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.
³ Johns Hopkins Drug Discovery Program, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA; Department of Chemistry, McDaniel College, 2 College Hill, Westminster, MD 21157, USA.
⁴ Johns Hopkins Drug Discovery Program, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA; Department of Molecular and Comparative Pathobiology, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA.
⁵ 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. Electronic address: ttsukamoto@jhmi.edu.

Abstract

A series of 3-substituted 5-hydroxy-1,2,4-triazin-6(1H)-one derivatives were designed and synthesized 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 plasma d-serine levels following its co-administration with d-serine compared to the oral administration of d-serine alone.

Keywords: Flavoenzyme; Pharmacokinetics; Schizophrenia; d-Amino acid oxidase; d-Serine.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
D-Amino-Acid Oxidase / antagonists & inhibitors*
D-Amino-Acid Oxidase / metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology*
Humans
Mice
Microsomes, Liver / chemistry
Microsomes, Liver / metabolism
Molecular Structure
Serine / blood
Structure-Activity Relationship
Triazines / chemistry
Triazines / metabolism
Triazines / pharmacology*

Substances

5-hydroxy-1,2,4-triazin-6(1H)-one
Enzyme Inhibitors
Triazines
Serine
D-Amino-Acid Oxidase

Abstract

Publication types

MeSH terms

Substances

Grants and funding