Peptide and peptide analog protease inhibitors

A method of modulating the processing of amyloid precursor protein (APP), comprising contacting a composition containing APP under conditions in which APP is processed with a compound of the formula:

• ##STR6## or a hydrate, isostere, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, with the proviso that:
• (1) at least one of R.sub.1 and R.sub.3 is not a side chain of a naturally-occurring .alpha.-amino acid;
• and (2) when X is an aldehyde, R.sub.1 cannot be the side chain of norleucine or norvaline, wherein:
• R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.8, R.sub.A, R.sub.B, X, Q and n are selected from among (i), (ii) or (iii) as follows:
• (i) R.sub.1, R.sub.3 and R.sub.B are each independently selected from the group consisting of a side chain of a naturally occurring .alpha.-amino acid, H, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl, Y-substituted aryl, aralkyl, aralkenyl, aralkynyl, and Z-substituted heteroaryl, heteroaralkyl, heteroaralkenyl, in which Y is selected from the group consisting of halogen, lower alkyl, alkoxy, OH, haloalkyl, nitrile, S-alkyl, phenyl, and --NRR, R is H, alkyl, lower alkyl, OH or halo-lower alkyl, Z is lower alkyl or halo lower alkyl;
• R.sub.2, R.sub.4 and R.sub.8 are each independently selected from H and lower alkyl;
• Q is selected from the group consisting of --C(O)--, --O--C(O)--, --S(O).sub.2 -- and --HN--C(O)--;
• n is zero or one;
• R.sub.A is --(T).sub.m --(D).sub.m --R.sub.1 in which T is O or NH, and D is C.sub.1-4 alkyl or C.sub.2-4 alkene;
• and m is zero or one;
• X is selected from the group consisting of --(CH.sub.2).sub.r C(O)H, --(CH.sub.2).sub.r C(O)haloalkyl, --(CH.sub.2).sub.r C(O)(CH.sub.2).sub.r CHN.sub.2, --(CH.sub.2).sub.r C.tbd.N, --C(CH.sub.2).sub.r (O)C(CH.sub.2).sub.r (O)OR.sub.D, --(CH.sub.2).sub.r C(O)(CH.sub.2).sub.r C(O)NR.sub.D R.sub.D,
• --(CH.sub.2).sub.r CH(OH)(CH.sub.2).sub.r C(O)U, --(CH.sub.2).sub.r CH(OH)CH.sub.2 C(O)U, --(CH.sub.2).sub.r C(O)W and --(CH.sub.2).sub.r C(O)CH.sub.2 W, in which:
• R.sub.D is selected from H, alkyl, phenyl, benzyl and phenethyl;
• U is --OR.sub.D or --NR.sub.D R.sub.D, and W is --OR.sub.D, --SR.sub.D, --NR.sub.D R.sub.D, or a heterocyclic moiety, and r is 0-5;
• or
• (ii) R.sub.3, R.sub.4, R.sub.A, R.sub.B, Q, X and n are as defined in (i),
• R.sub.8 is H;
• and
• R.sub.1 and R.sub.2 are each independently selected as follows:
• (a) from lower alkyl, lower alkyl linked to a heteroatom, or a heteroatom, with the proviso when more than one heteroatom is present, there is at least one carbon atom between each heteroatom, and
• (b) R.sub.1 and R.sub.2 are unsubstituted or substituted with Y, and
• (c) together with the atoms to which they are attached form a 4-6 membered heterocyclic moiety;
• or
• (iii) R.sub.1, R.sub.2, R.sub.8, X, Q and n are as defined in (i);
• R.sub.3 and R.sub.4 are each independently selected as follows:
• (a) from lower alkyl, lower alkyl linked to a heteroatom, or a heteroatom, with the proviso when more than one heteroatom is present, there is at least one carbon atom between each heteroatom, and
• (b) R.sub.3 and R.sub.4 are unsubstituted or substituted with Y, and
• (c) together with the atoms to which they are attached form a 4-6 membered heterocyclic moiety;
• whereby:
• (a) the formation of A.beta. peptide is decreased, or
• (b) the formation of .alpha.-sAPP is increased,
• relative to the amounts formed in the absence of the compound.