Nanomolar, non-peptide inhibitors of cathepsin D

A method of inhibiting cathepsin D, said method comprising contacting cathepsin with a compound having the formula:

• wherein:
• R.sub.1, R.sub.2 and R.sub.3 alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxyalkyl, substituted aryloxyalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycles, substituted heterocycles, heterocyclicalkyl and substituted heterocyclicalkyl;
• R.sub.5 and R.sub.6 are independently selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxyalkyl and substituted aryloxyalkyl;
• or R.sub.5 and R.sub.6 and the carbons to which they are bound join to form an optionally substituted carbocyclic or heterocyclic fused ring system having a total of 9- or 10-ring atoms within said fused heterocyclic ring system, said heterocyclic fused ring system containing at least one member selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom.

A method of inhibiting cathepsin D in living cells, said method comprising contacting said cells with an effective amount of a compound having the formula:

• wherein:
• R.sub.1, R.sub.2 and R.sub.3 alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxyalkyl, substituted aryloxyalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycles, substituted heterocycles, heterocyclicalkyl and substituted heterocyclicalkyl;
• R.sub.5 and R.sub.6 are independently selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxyalkyl and substituted aryloxyalkyl;
• or R.sub.5 and R.sub.6 and the carbons to which they are bound join to form an optionally substituted carbocyclic or heterocyclic fused ring system having a total of 9- or 10-ring atoms within said fused heterocyclic ring system, said heterocyclic fused ring system containing at least one member selected from the group consisting of a nitrogen atom an oxygen atom and a sulfur atom.

A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a cathepsin D inhibitor having the formula:

• wherein:
• R.sub.1, R.sub.2 and R.sub.3 alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxyalkyl, substituted aryloxyalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycles, substituted heterocycles, heterocyclicalkyl and substituted heterocyclicalkyl;
• provided R.sub.2 is not a radical which is a nitrogen-bonded cyclic .alpha.-amino acid or ester thereof,
• R.sub.5 and R.sub.6 are independently selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxyalkyl and substituted aryloxyalkyl;
• or R.sub.5 and R.sub.6 and the carbons to which they are bound join to form an optionally substituted carbocyclic or heterocyclic fused ring system having a total of 9- or 10-ring atoms within said fused heterocyclic ring system, said heterocyclic fused ring system containing at least one member selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom.