Thiol-based NAALADase inhibitors

1. A compound of formula II

or a pharmaceutically acceptable equivalent of said compound, wherein:

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are independently hydrogen or C 1 –C 3 alkyl; and

A 1 , A 2 , A 3 , A 4 and A 5 are independently hydrogen, C 1 –C 6 alkyl, C 1 –C 6 alkoxy, C 1 –C 3 perhaloalkyl, phenyl, phenoxy, benzyl, benzyloxy, hydroxy, halo, cyano, nitro, —SO 2 R 9 , —(C═O)NR 9 R 10 , —(C═O)NR 9 (CH 2 ) n COOH, —NR 9 (C═O)R 10 , —(CH 2 ) n COOH or —COOH, or any adjacent two of A 1 , A 2 , A 3 , A 4 and A 5 form with the benzene ring a fused 5- or 6-membered carbocyclic or heterocyclic aromatic ring, said heterocyclic aromatic ring containing 1 or 2 oxygen, nitrogen and/or sulfur heteroatom(s);

R 9 and R 10 are independently hydrogen, C 1 –C 6 alkyl, phenyl or benzyl; and

n is 1–3;

provided that if A 1 , A 3 and A 5 are independently hydrogen, C 1 –C 6 alkyl, C 1 –C 6 alkoxy, halo, nitro, phenyl, phenoxy, benzyl, benzyloxy or —COOH, then neither A 2 nor A 4 are —COOH; and provided that if any adjacent two of A 3 , A 4 and A 5 form with the benzene ring a fused 5- or 6-membered carbocyclic or heterocyclic aromatic ring, said heterocyclic aromatic ring containing 1 or 2 oxygen, nitrogen and/or sulfur heteroatom(s), then A 2 is not —COOH.

2. The compound of claim 1 , wherein:

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each hydrogen;

A 1 , A 2 , A 3 , A 4 and A 5 are independently hydrogen, C 1 –C 4 alkyl, C 1 –C 2 alkoxy, C 1 –C 2 perhaloalkyl, phenyl, phenoxy, hydroxy, halo, cyano, nitro, —SO 2 R 9 , —(C═O)NR 9 R 10 , —(C═O)NR 9 (CH 2 )COOH, —NR 9 (C═O)R 10 , —(CH 2 )COOH; and

R 9 and R 10 are independently hydrogen, methyl or benzyl.

3. The compound of claim 1 , wherein any adjacent two of A 1 , A 2 , A 3 , A 4 and A 5 form with the benzene ring a fused 5-or 6-membered carbocyclic or heterocyclic aromatic ring, said heterocyclic aromatic ring containing 1 or 2 oxygen, nitrogen and/or sulfur heteroatom(s).

4. The compound of claim 1 , wherein said compound is selected from the group consisting of:

alpha-(3-mercaptopropyl)-3-(trifluoromethyl)-benzenepropanoic acid;

alpha-(3-mercaptopropyl)-benzenepropanoic acid;

4-hydroxy-alpha-(3-mercaptopropyl)-benzenepropanoic acid;

2,3,4,5,6-pentafluoro-alpha-(3-mercaptopropyl)-benzenepropanoic acid;

4-carboxy-alpha-(3-mercaptopropyl)-benzenepropanoic acid;

alpha-(3-mercaptopropyl)-4-(methylsulfonyl)-benzenepropanoic acid;

2-cyano-alpha-(3-mercaptopropyl)-benzenepropanoic acid;

2-(aminocarbonyl)-alpha-(3-mercaptopropyl)-benzenepropanoic acid;

alpha-(3-mercaptopropyl)-2,5-dimethoxy-benzenepropanoic acid;

alpha-(3-mercaptopropyl)-3-phenoxy-benzenepropanoic acid;

alpha-(3-mercaptopropyl)-4-phenyl-benzenepropanoic acid;

4-(acetylamino)-alpha-(3-mercaptopropyl)-benzenepropanoic acid;

4-(carboxymethyl)-alpha-(3-mercaptopropyl)-benzenepropanoic acid;

4-carboxy-alpha (3-mercaptopropyl)-1-naphthalenepropanoic acid;

2-carboxy-alpha-(3-mercaptopropyl)-benzenepropanoic acid;

4-carboxy-2,3,5,6-tetrafluoro-alpha-(3-mercaptopropyl)-benzenepropanoic acid;

alpha-(3-mercaptopropyl)-2-naphthalenepropanoic acid;

2-chloro-alpha-(3-mercaptopropyl)-benzenepropanoic acid;

alpha-(3-mercaptopropyl)-3-[[(phenylmethyl)amino]-carbonyl]benzenepropanoic acid;

3-[[(carboxymethyl)amino]carbonyl]-alpha-(3-mercaptopropyl)-benzenepropanoic acid;

3-bromo-4-carboxy-alpha-(3-mercaptopropyl)-benzenepropanoic acid;

alpha-(3-mercaptopropyl)-3-phenyl-benzenepropanoic acid;

3-(1,1-dimethylethyl)-alpha-(3-mercaptopropyl)-benzenepropanoic acid; and

pharmaceutically acceptable equivalents.

5. The compound of claim 1 , wherein said compound is an enantiomer or an enantiomer-enriched mixture.

6. A method for inhibiting NAALADase enzyme activity, treating a glutamate abnormality, effecting a neuronal activity, treating a prostate disease, treating cancer, inhibiting angiogenesis or effecting a TGF-β activity, comprising administering to a mammal in need of such inhibition, treatment or effect, an effective amount of a compound of claim 1 .

7. 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 an effective amount of a compound of claim 1 , 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.

8. A method for detecting a disease, disorder or condition where NAALADase levels are altered in a mammal, comprising:

(i) labeling a compound of claim 6 with an effective amount of an imaging reagent;

(ii) administering to said mammal an effective amount of the labeled compound;

(iii) allowing said labeled compound to localize and bind to NAALADase present in said 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.

9. A diagnostic kit for detecting a disease, disorder or condition where NAALADase levels are altered, comprising a compound of claim 6 labeled with a marker.

10. A pharmaceutical composition comprising:

(i) an effective amount of a compound of claim 1 ; and

(ii) a pharmaceutically acceptable carrier.