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US 2006/0234944 A1Published application
Beta-secretase inhibitors and methods of use
AssigneesOklahoma Medical Reseach Foundation, The Board of Trustees of the University of Illinois
InventorsArun Ghosh, Jordan Tang, Geoffrey Bilcer, Wanpin Chang, Lin Hong, Gerald Koelsch, Jeff Loy, Robert Turner III
Life of this patent
Estimating the term…
Abstract
Compounds inhibit memapsin 2 β-secretase activity and selectively inhibit memapsin 2 β-secretase activity relative to memapsin 1 β-secretase activity. The compounds are employed in methods to inhibit memapsin 2 β-secretase activity, in the treatment of Alzheimer's disease, in the inhibition of hydrolysis of a β-secretase site of a β-amyloid precursor protein and to decrease β-amyloid protein in in vitro samples and in mammals. Proteins of memapsin 2 associated with compounds of the invention are crystallized.
Claims121
A compound represented by the following structural formula:
- wherein:
- Y is a carrier molecule;
- Z is a covalent bond, —OP(O)−2O—, —C(O)OR33—, —C(O)NHR33— or an amino acid sequence cleavable by a hydrolase;
- R33 is a bond or an alkylene;
- k is 0 or an integer from 1 to about 100;
- r is an integer from 1 to about 100;
- and
- A1 for each occurrence is a compound represented by the following structural formula:
- or optical isomers, diastereomers, or pharmaceutically acceptable salts thereof, wherein:
- X is C═O or S(O)n;
- n is 1 or 2;
- P1 is an aliphatic group, a hydroxyalkyl, an aryl, an aralkyl, a heterocycloalkyl, or an alkylsulfanylalkyl;
- P2, P1′, and P2′ are each, independently, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted heterocycle, or a substituted or unsubstituted heterocycloalkyl;
- R is —H;
- R1 is a substituted or unsubstituted aliphatic group, a substituted or unsubstituted alkoxy, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted heterocyclooxy, a substituted or unsubstituted heterocycloalkoxy, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted heteroaralkoxy, or —NR5R6;
- or R1, together with X, is a peptide or Y-Z-;
- R4 is H;
- or R4 and P1′, together with the atoms connecting R4 and P1′, form a five or six membered heterocycle;
- R2 and R3 are each, independently, selected from the group consisting of H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted heteroaryl, and a substituted or unsubstituted heteroaralkyl;
- or one of R2 and R3, together with the nitrogen to which it is attached, is a peptide or a Y-Z-;
- or R2 and R3, together with the nitrogen to which they are attached, form a substituted or unsubstituted heterocycle or a substituted or unsubstituted heteroaryl;
- and
- R5 and R6 are each, independently, H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heteroaralkyl;
- or
- R and one of R5 or R6, together with X and the nitrogen atoms to which they are attached, form a 5-, 6-, or 7-membered substituted or unsubstituted heterocycle or substituted or unsubstituted heteroaryl ring,
- provided that the compound is not one of the following compounds:
23 more elements
A compound represented by the following structural formula:
- wherein:
- Y is a carrier molecule;
- Z is a bond, —OP(O)−2O—, —C(O)OR33—, —C(O)NHR33— or an amino acid sequence cleavable by a hydrolase;
- R33 is a bond or an alkylene;
- k is 0 or an integer from 1 to about 100;
- r is an integer from 1 to about 100;
- and
- A2 for each occurrence is a compound represented by the following structural formula:
- or optical isomers, diastereomers, or pharmaceutically acceptable salts thereof, wherein:
- X is C═O or S(O)n;
- n is 1 or 2;
- P1 is an aliphatic group, a hydroxyalkyl, an aryl, an aralkyl, a heterocycloalkyl, or an alkylsulfanylalkyl;
- P2, P1′, and P2′ are each, independently, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted heterocycle, or a substituted or unsubstituted heterocycloalkyl;
- R4 is H;
- or R4 and P1′, together with the atoms connecting R4 and P1′, form a five or six membered heterocycle;
- R2 and R3 are each, independently, selected from the group consisting of H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted heteroaryl, and a substituted or unsubstituted heteroaralkyl;
- or one of R2 and R3, together with the nitrogen to which they are attached, is a peptide or Y-Z-;
- or R2 and R3 together with the nitrogen to which they are attached form a substituted or unsubstituted heterocycle or a substituted or unsubstituted heteroaryl;
- and
- R19 is an aliphatic group substituted with one or more substituents, wherein at least one substituent is a substituent selected from the group consisting of —NR15C(O)R16, —NR15C(O)2R16 and —NR15S(O)2R16, wherein:
- R15 and R16 are each, independently, H, an aliphatic group, an aryl, an aralkyl, a heterocycle, a heterocycloalkyl, a heteroaryl or a heteroaralkyl, wherein the aliphatic group, aryl, aralkyl, heterocycle, heterocyclalkyl, heteroaryl or heteroaralkyl are optionally substituted with one or more substituents selected from the group consisting of an aliphatic group, hydroxy, —OR9, a halogen, a cyano, a nitro, —NR9R10, guanidino, —OPO3−2, —PO3−2, —OSO3−, —S(O)pR9, —OC(O)R9, —C(O)R9, —C(O)2R9, —NR9C(O)R10, —C(O)NR9R10, —OC(O)NR9R10, —NR9C(O)2R10, an aryl, a heteroaryl, a heteroaralkyl, and a heterocycle;
- and
- p is 0, 1, or 2,
- provided that when R19 is substituted with —NR15C(O)R16 or —NR15C(O)2R16, —NR2R3 is not a group having the following structural formula:
21 more elements
A compound represented by the following structural formula:
- wherein:
- Y is a carrier molecule;
- Z is a bond, —OP(O)−2O—, —C(O)OR33—, —C(O)NHR33— or an amino acid sequence cleavable by a hydrolase;
- R33 is a bond or an alkylene;
- k is 0 or an integer from 1 to about 100;
- r is an integer from 1 to about 100;
- and
- A3 for each occurrence is a compound represented by the following structural formula:
- or optical isomers, diastereomers, or pharmaceutically acceptable salts thereof, wherein:
- X is C═O or S(O)n;
- n is 1 or 2;
- P1 is an aliphatic group, a hydroxyalkyl, an aryl, an aralkyl, a heterocycloalkyl, or an alkylsulfanylalkyl;
- P2, P1′, and P2′ are each, independently, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted heterocycle, or a substituted or unsubstituted heterocycloalkyl;
- R is —H;
- R1 is a substituted or unsubstituted aliphatic group, a substituted or unsubstituted alkoxy, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted heterocyclooxy, a substituted or unsubstituted heterocycloalkoxy, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted heteroaralkoxy, or —NR5R6;
- R1, together with X, is a peptide or Y-Z-;
- R4 is H;
- or R4 and P1′, together with the atoms connecting R4 and P1′, form a five or six membered heterocycle;
- R2 and R3 are each, independently, selected from the group consisting of H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted heteroaryl, and a substituted or unsubstituted heteroaralkyl;
- or one of R2 and R3, together with the nitrogen to which they are attached, is a peptide or Y-Z-;
- or R2 and R3, together with the nitrogen to which they are attached, form a substituted or unsubstituted heterocycle or a substituted or unsubstituted heteroaryl;
- and
- R5 and R6 are each, independently, H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heteroaralkyl;
- or
- R and one of R5 or R6, together with X and the nitrogen atoms to which they are attached, form a 5-, 6-, or 7-membered substituted or unsubstituted heterocycle or substituted or unsubstituted heteroaryl ring, wherein the compound selectively inhibits hydrolysis of a memapsin 2 β-secretase site relative to a memapsin 1 β-secretase site.
22 more elements
A compound represented by the following structural formula:
- wherein:
- Y is a carrier molecule;
- Z is a bond, —OP(O)−2O—, —C(O)OR33—, —C(O)NHR33— or an amino acid sequence cleavable by a hydrolase;
- R33 is a bond or an alkylene;
- k is 0 or an integer from 1 to about 100;
- r is an integer from 1 to about 100;
- and
- A4 for each occurrence is a compound represented by the following structural formula:
- or optical isomers, diastereomers, or pharmaceutically acceptable salts thereof, wherein:
- X is C═O or S(O)n;
- n is 1 or 2;
- P1 is an aliphatic group, a hydroxyalkyl, an aryl, an aralkyl, a heterocycloalkyl, or an alkylsulfanylalkyl;
- P2, P1′, and P2′ are each, independently, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted heterocycle, or a substituted or unsubstituted heterocycloalkyl;
- R is —H;
- R4 is H;
- or R4 and P1′, together with the atoms connecting R4 and P1′, form a five or six membered heterocycle;
- R2 and R3 are each, independently, selected from the group consisting of H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted heteroaryl, and a substituted or unsubstituted heteroaralkyl;
- or one of R2 or R3, together with the nitrogen to which they are attached, is a peptide or Y-Z-;
- or R2 and R3 together with the nitrogen to which they are attached form a substituted or unsubstituted heterocycle or a substituted or unsubstituted heteroaryl;
- R18 is a substituted or unsubstituted heteroaralkoxy, a substituted or unsubstituted heteroaralkyl, or —NR20R21;
- and
- R20 and R2, are each, independently, —H or a substituted or unsubstituted heteroaralkyl;
- or
- R and one of R20 or R21, together with X and the nitrogen atoms to which they are attached, form a 5-, 6-, or 7-membered substituted or unsubstituted heterocycle or substituted or unsubstituted heteroaryl ring.
21 more elements
A compound represented by the following structural formula:
- wherein:
- Y is a carrier molecule;
- Z is a bond, —OP(O)−2O—, —C(O)OR33—, —C(O)NHR33— or an amino acid sequence cleavable by a hydrolase;
- R33 is a bond or an alkylene;
- k is 0 or an integer from 1 to about 100;
- r is an integer from 1 to about 100;
- and
- A5 for each occurrence is, independently, a compound selected from the group consisting of:
- or pharmaceutically acceptable salts thereof.
6 more elements
A crystallized complex comprising:
- a) a protein that includes an amino acid sequence selected from the group consisting of amino acid residues 1-456 SEQ ID NO:
- 8, amino acid residues 16-456 of SEQ ID NO:
- 8, amino acid residues 27-456 of SEQ ID NO:
- 8, amino acid residues 43-456 of SEQ ID NO:
- 8 and amino acid residues 45-456 of SEQ ID NO:
- 8;
- and
- b) a compound in association with said protein, wherein said compound is in association with said protein at an S3′ binding pocket, an S4′ binding pocket or an S4 binding pocket.
5 more elements
A crystallized complex comprising:
- a) a protein that includes an amino acid sequence selected from the group consisting of amino acid residues 1-456 SEQ ID NO:
- 8, amino acid residues 16-456 of SEQ ID NO:
- 8, amino acid residues 27-456 of SEQ ID NO:
- 8, amino acid residues 43-456 of SEQ ID NO:
- 8 and amino acid residues 45-456 of SEQ ID NO:
- 8;
- and
- b) a compound in association with said protein, wherein said compound is in association with said protein at an S3 binding pocket.
5 more elements
Dependencies are inferred from the claim text.