Treatment of CNS disorders using D-amino acid oxidase and D-aspartate oxidase antagonists
AssigneeGenset S.A.
InventorsDaniel Cohen, llya Chumakov
Life of this patent
Estimating the term…
Abstract
Compounds that are antagonists of D-amino acid oxidase and D-aspartate oxidase, methods of treating CNS disorders including bipolar disorder, psychosis and schizophrenia using the compounds, and pharmaceutically acceptable compositions that contain the antagonists are disclosed.
Claims13
A method of assessing a candidate molecule for the treatment of a CNS disorder, said method comprising:
- a) providing a test DAO-inhibitor or DDO-inhibitor compound;
- and
- b) administering said compound to an animal model of schizophrenia or bipolar disorder,
- wherein a determination that said compound ameliorates a characteristic representative of a CNS disorder in said animal model indicates that said compound is a candidate molecule for the treatment of a CNS disorder;
- and alternatively one or more of the following:
- i.) wherein said compound selectively bind to said polypeptide;
- ii.) wherein said compound selectively inhibits the activity of said polypeptide;
- iii.) wherein said compound is capable of inhibiting the oxidation or degradation of a D-amino acid selected from the group consisting of D-Met, D-Pro, D-Phe, D-Tyr, D-Ile, D-Leu, D-Ala, D-Val, D-Ser, D-Arg, D-His, D-norleucine, D-Trp, D-Ornithine, cis-4-hydroxy-D-proline, D-Thr, D-Trp-methyl ester, N-acetyl-D-Ala, D-Lys, D-Asp, D-Glu, D-Asn, D-Gln, D-Asp-dimethyl-ester and N-methyl-D-Asp;
- and further alternatively wherein the compound of claim iii is capable of inhibiting the oxidation or degradation of D-serine.
A method of diagnosing, detecting a predisposition to or susceptibility to schizophrenia, depression or bipolar disorder in a subject, comprising
- (a) obtaining a nucleic acid sample from said subject;
- and
- (b) determining the identity of a nucleotide at a DAO-related polymorphism, or the complement thereof in said biological sample.
A isolated or purified nucleic acid encoding a DAO polypeptide or DAO polypeptide selected from the group consisting of:
- (i) a nucleic acid molecule encoding a polypeptide comprising an amino acid sequence selected from the group of sequences consisting of SEQ ID NOs 8 to 10;
- and
- (ii) a nucleic acid molecule comprising a nucleic acid sequence selected from the group of sequences consisting of SEQ ID NOs 1 to 6, or a sequence complementary thereto;
- (iii) a purified or isolated DAO polypeptide comprising an amino acid sequence selected from the group of sequences consisting of SEQ ID NOs 8 to 10.
- (iv) a polypeptide encoded by a nucleic acid molecule comprising a nucleic acid sequence selected from the group of sequences consisting of SEQ ID NOs 1 to 6, or a sequence complementary thereto.
A method of identifying a candidate molecule for the treatment of a CNS disorder, said method comprising:
- (a) contacting a DAO or DDO polypeptide or a biologically active fragment thereof with a test compound;
- (b) determining whether said compound (i) binds to said polypeptide, or (ii) inhibits the activity of said polypeptide;
- and
- (c) if said compound binds to said polypeptide or inhibits said polypeptide, administering said compound to an animal model of schizophrenia, depression or bipolar disorder,
- wherein a determination that said compound ameliorates a characteristic representative of CNS disorder in said animal model indicates that said compound is a candidate molecule for the treatment of a CNS disorder.
Dependencies are inferred from the claim text.