The present invention relates to new compounds, pharmaceutical compositions and diagnostic kits comprising such compounds, and methods of using such compounds for inhibiting NAALADase enzyme activity, detecting diseases where NAALADase levels are altered, effecting neuronal activity, effecting TGF-xcex2 activity, inhibiting angiogenesis, and treating glutamate abnormalities, neuropathy, pain, compulsive disorders, prostate diseases, cancers, glaucoma, and retinal disorders.
The NAALADase enzyme, also known as prostate specific membrane antigen (xe2x80x9cPSMxe2x80x9d or xe2x80x9cPSMAxe2x80x9d) and human glutamate carboxypeptidase II (xe2x80x9cGCP IIxe2x80x9d), catalyzes the hydrolysis of the neuropeptide N-acetyl-aspartyl-glutamate (xe2x80x9cNAAGxe2x80x9d) to N-acetyl-aspartate (xe2x80x9cNAAxe2x80x9d) and glutamate. Based upon amino acid sequence homology, NAALADase has been assigned to the M28 family of peptidases.
Studies suggest NAALADase inhibitors may be effective in treating ischemia, spinal cord injury, demyelinating diseases, Parkinson""s disease, Amyotrophic Lateral Sclerosis (xe2x80x9cALSxe2x80x9d), alcohol dependence, nicotine dependence, cocaine dependence, cancer, neuropathy, pain and schizophrenia, and in inhibiting angiogenesis. In view of their broad range of potential applications, a need exists for new NAALADase inhibitors and pharmaceutical compositions comprising such compounds.
The present invention relates to a compound of formula Ia or a pharmaceutically acceptable equivalent: 
wherein:
R1, R2, R3, and R4 are independently hydrogen or C1-C3 alkyl; and
A1, A2, A3, and A4 are independently hydrogen, C1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, aryl, heteroaryl, carbocycle, heterocycle, halo, hydroxy, sulfhydryl, nitro, amino, cyano, isocyano, thiocyano, isothiocyano, formamido, thioformamido, sulfo, sulfino, C1-C9 alkylsulfonyl, C1-C9 alkoxy, C2-C9 alkenoxy, phenoxy, or benzyloxy,
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, alkoxy, alkenoxy, phenoxy, and benzyloxy are independently unsubstituted or substituted with one or more substituent(s).
In one embodiment, R1, R2, R3, R4, A2, A3, and A4 are hydrogen; and A1 is hydrogen, xe2x80x94(CH2)nxe2x80x94W, or xe2x80x94Yxe2x80x94(CH2)nxe2x80x94W, wherein: n is 0-3; Y is O, S, or NR wherein R is hydrogen or C1-C4 alkyl; and W is C1-C6 alkyl or phenyl, wherein W is unsubstituted or substituted with C1-C4 alkyl, C1-C4 alkoxy, carboxy, or halo.
The present invention further relates to a compound of formula Ib or a pharmaceutically acceptable equivalent: 
wherein A1, A2, A3 and A4 are independently hydrogen, C1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, aryl, heteroaryl, carbocycle, heterocycle, halo, hydroxy, sulfhydryl, nitro, amino, cyano, isocyano, thiocyano, isothiocyano, formamido, thioformamido, sulfo, sulfino, C1-C9 alkylsulfonyl, C1-C9 alkoxy, C2-C9 alkenoxy, phenoxy, or benzyloxy,
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, alkoxy, alkenoxy, phenoxy, and benzyloxy are independently unsubstituted or substituted with one or more substituent(s),
wherein if A1 is chloro, fluoro, amino, or thiomethyl then A2, A3, and A4 may not all be hydrogen,
and wherein at least one of A1, A2, A3, and A4 is not hydrogen.
In one embodiment, A2, A3, and A4 are hydrogen; and A1 is xe2x80x94(CH2)nxe2x80x94Ar or xe2x80x94Yxe2x80x94(CH2)nxe2x80x94Ar, wherein n is 0-3, Y is O, S, or NR wherein R is hydrogen or C1-C4 alkyl, and Ar is phenyl, unsubstituted or substituted with C1-C4 alkyl, carboxy, or halo.
The present invention further relates to a compound of formula I: 
or a pharmaceutically acceptable equivalent, wherein:
X is xe2x80x94(CR1R2)nSH, xe2x80x94O(CR1R2)2SH, xe2x80x94S(CR1R2)2SH, or xe2x80x94NR(CR1R2)2SH;
n is 1-3; and
R, R1, R2, A1, A2, A3 and A4 are independently hydrogen, C1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, aryl, heteroaryl, carbocycle, heterocycle, halo, hydroxy, sulfhydryl, nitro, amino, cyano, isocyano, thiocyano, isothiocyano, formamido, thioformamido, sulfo, sulfino, C1-C9 alkylsulfonyl, C1-C9 alkoxy, C2-C9 alkenoxy, phenoxy, or benzyloxy,
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, alkoxy, alkenoxy, phenoxy, and benzyloxy are independently unsubstituted or substituted with one or more substituent(s).
Additionally, the present invention relates to a method for inhibiting NAALADase enzyme activity, detecting diseases where NAALADase levels are altered, effecting neuronal activity, effecting TGF-xcex2, activity, inhibiting angiogenesis, or treating glutamate abnormalities, neuropathy, pain, compulsive disorders, prostate diseases, cancers, glaucoma, or retinal disorders, comprising administering to a mammal in need of such inhibition, treatment or effect, an effective amount of a compound of formula I, Ia, or Ib, as defined above.
The present invention further relates to a method for detecting a disease, disorder or condition where NAALADase levels are altered, comprising:
(i) contacting a sample of bodily tissue or fluid with a compound of formula I, Ia, or Ib, as defined above, wherein said compound binds to any NAALADase in said sample; and
(ii) measuring the amount of any NAALADase bound to said sample, wherein the amount of NAALADase is diagnostic for said disease, disorder, or condition.
The present invention also relates to a method for detecting a disease, disorder or condition where NAALADase levels are altered in an animal or a mammal, comprising:
(i) labeling a compound of formula I, Ia, or Ib, as defined above, with an imaging reagent;
(ii) administering to said animal or mammal an effective amount of the labeled compound;
(iii) allowing said labeled compound to localize and bind to NAALADase present in said animal or mammal; and
(iv) measuring the amount of NAALADase bound to said labeled compound, wherein the amount of NAALADase is diagnostic for said disease, disorder, or condition.
Additionally, the present invention further relates to a diagnostic kit for detecting a disease, disorder, or condition where NAALADase levels are altered, comprising a compound of formula I, Ia, or Ib, as defined above, labeled with a marker.
Finally, the present invention relates to a pharmaceutical composition comprising:
(i) an effective amount of a compound of formula I, Ia, or Ib, as described above; and
(ii) a pharmaceutically acceptable carrier.