Claims
- 1. 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.
- 2. The method of claim 1, wherein said test compound is selected from the group consisting of:
(1) a compound represented by the structure comprising: 99or a pharmaceutically acceptable salt thereof, wherein:
a) A is alkyl such as methyl, ethyl, propyl or butyl; branched chain alkyl such as isobutyl, isopropyl, isopentyl or cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl. Such groups may themselves be substitued with C1-C6 alkyl, halo, hydroxyl or amino; b) X is O or N; c) Ar is an aromatic mono-, bi- or tricyclic fused heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to five position(s) with hydrogen, halogen, hydroxyl, —CN, COR2, —CONR2R3, —S(O), R2, —OPO(OR2)OR3, —PO(OR3)R3, —OC(O)NR2R3, —COOR2, —CONR2R3, —SO3H, —NR2R3, —NR2COR3, —NR3COOR3, —SO2NR2R3, —N(R2)SO2R3, —NR2CONR2R2, —SO2NHCOR2, —CONHSO2R2, —SO2NHCN, —OR1, C1-C6 straight or branched chain alkyl or alkenyl, or C1-C6 branched or straight chain alkyl or alkenyl which is substituted with one or more, halogen, hydroxyl, amino, carboxy, carboxamide, nitrile, nitro, alkoxy, trifluoromethyl, sulfur, sulfonate, phosphonate, phosphate, Ar1, N3 or a combination thereof and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof; d) R4 is H, alkyl, Ar1, O, substituted alkyl; e) R1 is (C1-C6) alkyl, Ar1, (C1-C4) alkoxycarbonylmethyl, substituted alkyl; f) R2 and R3 are each, independently, hydrogen, C1-C6 straight or branched chain alkyl or alkenyl, or C1-C6 branched or straight chain alkyl or alkenyl which is substituted with one or more, halogen, hydroxyl, amino, carboxy, carboxamide, nitrile, nitro, alkoxy, trifluoromethyl, sulfur, sulfonate, phosphonate, phosphate, Ar1, or N3; and g) Ar1 is a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 3-7 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof; (2) a compound represented by the structure comprising: 100wherein:
a) A and B consist of C or N and D may contain 0-2 members consisting of C or N; b) W is C1-C4 alkyl such as (CH2)n, branched chain alkyl; c) n is 0-4. Further, when n=0 it is assumed that —NHR2 is covalently bound to B; d) X is O or N; e) R2 is H, alkyl, Ar1, or O substituted alkyl; f) R1 is (C1-C6) alkyl Ar1, (C1-C4) alkoxycarbonylmethyl, or substituted alkyl; g) Ar is an aromatic mono-, bi- or tricyclic fused heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to six position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, C3-C6 cycloalkyl or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof; and h) Ar1 is a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 3-7 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof; and (3) a compound represented by the structure comprising: 101wherein:
a) A, G, K, J, E are members of a six membered carbo or heterocyclic aromatic ring, wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of C, N and a combination thereof, b) A, G, K, J, E may each independently be unsubstituted or substituted with hydrogen, halogen, hydroxyl, —CN, COR2, —CONR2R3, —S(O)nR2, —OPO(OR2)OR3, —PO(OR3)R3, —OC(O)NR2R3, —COOR2, —CONR2R3, —SO3H, —NR2R3, —NR2COR3, —NR3COOR3, —SO2NR2R3, —N(R2)SO2R3, —NR2CONR2R2, —SO2NHCOR2, —CONHSO2R2, —SO2NHCN, —OR1, C1-C6 straight or branched chain alkyl or alkenyl, or C1-C6 branched or straight chain alkyl or alkenyl which is substituted with one or more halogen, hydroxyl, amino, carboxy, carboxamide, nitrile, nitro, alkoxy, trifluoromethyl, sulfur, sulfonate, phosphonate, phosphate, Ar1, or N3; c) R1 is CN, COR2, —CONR2R3, —S(O)nR2, —OPO(OR2)OR3, —PO(OR3)R3, —OC(O)NR2R3, —COOR2, —CONR2R3, —SO3H, —NR2R3, —NR2COR3, —NR3COOR3, —SO2NR2R3, —N(R2)SO2R3, —NR2CONR2R2, —SO2NHCOR2, —CONHSO2R2, —SO2NHCN, SCN, COCO2H, C1-C6 straight or branched chain alkyl or alkenyl, or C1-C6 branched or straight chain alkyl or alkenyl which is substituted with one or more halogen, hydroxyl, amino, carboxy, carboxamide, nitrile, nitro, alkoxy, trifluoromethyl, sulfur, sulfonate, phosphonate, phosphate, Ar1, or N3; d) W is N, (CH2)x, or —NCH2; e) x=0-4; f) n=0-2; g) R2 and R3 are each, independently, hydrogen, C1-C6 straight or branched chain alkyl or alkenyl, or C1-C6 branched or straight chain alkyl or alkenyl which is substituted with one or more halogen, hydroxyl, amino, carboxy, carboxamide, nitrile, nitro, alkoxy, trifluoromethyl, sulfur, sulfonate, phosphonate, phosphate, Ar1, or N3; and h) Ar1 is a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.
- 3. The method of claim 1, wherein said test compound is selected from the group consisting of
(1) a compound represented by the structure comprising: 102wherein:
a) W=(CH2)n; b) n=0-5; c) Z is O or hydroxyl; d) Y═H, Ar1, R4(CH2)x, R1S(CH2)x—, R1SO(CH2)x—, R1SO2(CH2)x—, R1SO3(CH2)x—, HNR1SO2(CH2)x—, R1R2N(CH2)x, R1O(CH2)—, CF3, or OH; e) x=0-6; f) R1, R2 and R3 are each independently hydrogen, C1-C6 straight or branched chain alkyl or C1-C6 branched or straight chain alkyl substituted with one or more halogen, hydroxyl, amino, carboxy, carboxamide, nitrile, nitro, alkoxy, trifluoromethyl, sulfur, sulfonate, phosphonate, phosphate, or Ar1; g) R4 is halogen, CN, N3, C1-C6 straight or branched chain alkyl or C1-C6 branched or straight chain alkyl substituted with one or more halogen, hydroxyl, nitro, alkoxy, trifluoromethyl, sulfonate, phosphonate, phosphate, Ar1, —COR1, —COOR1, —CONR1R2, CN, —NR1, —NR1R2, —SR1, —SO2NHCN, or N3; and h) Ar1 is a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof; and (2) a compound represented by the structure comprising: 103wherein:
a) Y is Ar1; b) Z is a carbonyl or hydroxyl; c) W is (CH2)n wherein (n=0,1, or 2) and R3=H; and d) Ar1 is a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.
- 4. The method of claim 1, wherein said test compound is represented by the structure comprising:
- 5. The method of claim 4, wherein said compound is cystathionine ketimine or cyclothionine
- 6. The method of claim 1, wherein said test compound is represented by the structure comprising:
- 7. The method of claim 6, wherein said compound is selected from the group consisting of: Aminoethylcysteine-ketimine (2H-1,4-thiazine-5,6-dihydro-3-carboxylic acid), Thiomorpholine-2-carboxylic acid, Lanthionine ketimine, and 1,4-Thiomorpholine-3,5-dicarboxylic acid.
- 8. The method of claim 1, wherein said test compound is selected from the group consisting of:
(1) a compound represented by the structure comprising: 106wherein:
a) Z is O or NH; b) R1 is (C1-C6) alkyl, Ar1, or (C1-C4) alkoxycarbonylmethyl; c) X, Y, independently of one another, are H, Ar1, (C1-C6) alkyl (which can be interrupted or substituted by heteroatoms, such as N, P, O, S or Si, it being possible for the heteroatoms themselves to be substituted by (C1-C3) alkyl once or several times), (C2-C6) alkenyl, (C1-C6) haloalkyl,or halogen. When X and Y are each carbon they may be covalently joined to form a saturated or partially unsaturated carbocyclic compound of 3-8 members consisting independently of C, N, O, and S, further wherein ring members may themselves be unsubstituted or substituted with halo, hydroxyl, carboxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, substituted alkyl, Ar1 , or a combination thereof; d) R2 is H, alkyl, Ar1, or O substituted alkyl; and e) Ar1 is a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 3-7 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and any combination thereof; (2) a compound represented by the structure comprising: 107wherein:
a) *=asymmetric center and b) R1=(C1-C6) alkyl, Ar1, (C1-C4) alkoxycarbonylmethyl and c) X is H, (C1-C6) alkyl (which can be interrupted or substituted by heteroatoms, such as N, P, O, S or Si, it being possible for the heteroatoms themselves to be substituted by (C1-C3) alkyl once or several times), (C2-C6) alkenyl, (C1-C6) haloalkyl, halogen, or Ar1; d) R2 is H, alkyl, Ar1, or O substituted alkyl; e) Ar1 is a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 3-7 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and any combination thereof; (3) a compound represented by the structure comprising: 108wherein:
a) X and Y are each carbon; b) X and Y are connected by a saturated or partially saturated ring of 3-8 carbons and such a ring may itself be substituted in one to five position(s) with halo, hydroxyl, carboxy, amino, nitro, cyano, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, or substituted alkyl groups; c) R1 is (C1-C6) alkyl, Ar1, or (C1-C4) alkoxycarbonylmethyl; d) R2 is H, alkyl, Ar1, or O substituted alkyl; and e) Ar1 is a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 3-7 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and any combination thereof; and (4) a compound represented by the structure comprising: 109wherein:
a) X, Y, independently of one another, are H, Ar1, (C1-C6) alkyl (which can be interrupted or substituted by heteroatoms, such as N, P, O, S or Si, it being possible for the heteroatoms themselves to be substituted by (C1-C3) alkyl once or several times), (C2-C6) alkenyl, (C1-C6) haloalkyl, or halogen such as naphthyl or phenyl; b) R2 is H, alkyl, Ar1, or O substituted alkyl; and c) Ar1 is a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 3-7 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and any combination thereof.
- 9. The method of claim 1, wherein said test compound is represented by the structure comprising:
- 10. 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.
- 11. 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.
- 12. The method of claim 1, wherein said test compound (i) binds to a DAO or DDO polypeptide, or (ii) inhibits the activity of a DAO or DDO polypeptide.
- 13. 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.
RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. Ser. No. 10/051,681 claims priority from U.S. Provisional Patent Application Serial Nos. 60/261,883, filed Jan. 16, 2001; 60/305,445, filed Jul. 13, 2001; 60/345,211, filed Oct. 22, 2001; and 60/333,881 filed Nov. 19, 2001, which disclosures are hereby incorporated by reference in their entireties.
Provisional Applications (4)
|
Number |
Date |
Country |
|
60261883 |
Jan 2001 |
US |
|
60305445 |
Jul 2001 |
US |
|
60345211 |
Oct 2001 |
US |
|
60333881 |
Nov 2001 |
US |
Continuation in Parts (1)
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Number |
Date |
Country |
Parent |
10051681 |
Jan 2002 |
US |
Child |
10211160 |
Aug 2002 |
US |