Method for prophylactic treatment of alzheimer's disease using inhibitors of glutaminyl cyclase and glutamate cyclases
Provided herein are methods for treating and preventing neurodegenerative disease in a mammal by administering an inhibitor of glutaminyl cyclase (QC). Neurodegenerative diseases treatable or preventable according to methods described herein include mild cognitive impairment (MCI), Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, and Familial Danish Dementia.
1. A method of prophylactically treating Alzheimer's disease in a mammal, comprising
administering to a mammalian subject a therapeutically effective amount of at least one inhibitor of glutaminyl cyclase (QC) for specifically inhibiting conversion of N-terminal glutamic acid or glutamine residues to pyroglutamyl residues in at least one QC-substrate,
wherein,
the QC-inhibitor is a selective competitive QC-inhibitor; and
said competitive QC-inhibitor inhibits glutaminyl cyclase with a K i of 10 μM or less.
2. The method according to claim 1 wherein said at least one QC-substrate is selected from the group consisting of Aβ(3-40), Aβ(3-42), [Gln3]Aβ(3-40), [Gln3]Aβ(3-42), [Glu11]Aβ(11-40), [Glu11]Aβ(11-42), [Gln11]Aβ(11-40), [Gln11]Aβ(11-42), ABri, ADan, [Gln 1 ]Gastrins (17 and 34), [Gln 1 ]Neurotensin, [Gln 1 ]FPP, [Gln 1 ]TRH, [Gln 1 ]GnRH, [Gln 1 ]CCL 2, [Gln 1 ]CCL 7, [Gln 1 ]CCL 8, [Gln 1 ]CCL 13, [Gln 1 ]CCL 16, [Gln 1 ]CCL 18, [Gln 1 ]ELA, [Gln 1 ]Fractalkine, [Gln 1 ]Orexin A, [Gln 3 ]glucagon(3-29) and [Gln 5 ]substance P(5-11).
3. The method according to claim 1 wherein administration of the QC inhibitor results in suppression of myeloid progenitor cell proliferation.
4. The method of claim 1 , wherein said QC-inhibitor inhibits glutaminyl cyclase with a K i of 1 μM or less.
5. The method of claim 1 , wherein said QC-inhibitor inhibits glutaminyl cyclase with a K i of 0.1 μM or less.
6. The method of claim 1 , wherein said QC inhibitor or a pharmaceutically acceptable salt, solvate, stereoisomer or polymorph thereof is selected from
(i) a compound of formula 1*:
(ii) a compound of formula 1a,
wherein R is selected from the group consisting of:
Methyl;
tert-Butyl;
Benzyl;
Phenyl;
4-(fluoro)-phenyl;
4-(chloro)-phenyl;
4-(ethyl)-phenyl;
4-(trifluoromethyl)-phenyl;
4-(methoxy-carbonyl)-phenyl;
4-(acetyl)-phenyl;
4-(methoxy)-phenyl;
bicyclo[2.2.1]hept-5-en-2-yl;
3,4-(dimethoxy)-phenyl;
2,4-(dimethoxy)-phenyl;
3,5-(dimethoxy)-phenyl;
2-(methoxy-carbonyl)-phenyl;
4-(oxazol-5-yl)-phenyl;
4-(pyrazol-1-yl)-phenyl;
4-(isopropyl)-phenyl;
4-(piperidine-1-sulfonyl)-phenyl;
4-(morpholin-4-yl)-phenyl;
4-(cyano)-phenyl;
2,3-dihydro-benzo[1,4]dioxin-6-yl;
benzo[1,3]dioxol-5-yl;
3,4,5(trimethoxy)-phenyl;
3-(methoxy)-phenyl;
4-(ethoxy)-phenyl;
4-(benzyloxy)-phenyl;
4-(methoxy)-benzyl;
3,4-(dimethoxy)-benzyl;
2-(methoxy-carbonyl)-thiophene-3-yl;
3-(ethoxy-carbonyl)-4,5,6,7-tetrahydrobenzo[b]thio-phene2-yl;
2-(methoxy-carbonyl)-4-(methyl)-thiophene-3-yl;
Benzo[c][1,2,5]thiazol-4-yl;
Benzo[c][1,2,5]thiazol-5-yl;
5-(methyl)-3-(phenyl)isooxazol-4-yl;
3,5-(dimethyl)-isooxazol-4-yl;
4-(iodo)-phenyl;
4-(bromo)-phenyl;
4-(methyl)-phenyl;
Naphthalen-1-yl;
4-(nitro)-phenyl;
Butyl;
Cyclooctyl;
Furan-2-ylmethyl;
Tetrahydrofuran-2-ylmethyl;
Benzo[1,3]dioxol-5-ylmethyl;
2-(morpholin-4-yl)-ethyl;
4-(methylsulfanyl)-phenyl;
4-(dimethylamino)-phenyl;
4-(trifluoromethoxy)-phenyl;
Benzoyl; and
Pyridin-4-yl;
(iii) a compound of formula 1b,
wherein R 1 and R 2 are selected from the group consisting of:
R 1
R 2
Cyano
Methyl
Cyano
3,4-(dimethoxy)-phenyl
Cyano
2,4-(dimethoxy)-phenyl
Cyano
3,5-(dimethoxy)-phenyl
Cyano
2,3-dihydrobenzo[b][1,4]dioxin-
7-yl
Cyano
Benzo[d][1,3]dioxol-6-yl
Cyano
3,4,5-(trimethoxy)-phenyl
Cyano
3-(methoxy)-phenyl
Cyano
4-(ethoxy)-phenyl
Cyano
4-(benzyloxy)-phenyl
Cyano
Phenyl
Cyano
4-(methoxy)-phenyl
Cyano
4-(acetyl)-phenyl
Cyano
4-(nitro)-phenyl
Cyano
Benzyl
Cyano
Naphthalen-1-yl
Cyano
4-(fluoro)-phenyl
Cyano
4-(iodo)-phenyl
Cyano
4-(bromo)-phenyl
Cyano
Cyclooctyl
Cyano
tert-butyl
Cyano
4-(methyl)-phenyl
Cyano
4-(methylthio)-phenyl
Cyano
4-(ethyl)-phenyl
Cyano
4-(dimethylamino)-phenyl
Cyano
Butyl
Cyano
Trityl
Cyano
(Benzo[d][1,3]dioxol-6yl)methyl
Cyano
(tetrahydrofuran-2yl)methyl
Cyano
4-(trifluoromethyl)-phenyl
Cyano
(furan-2-yl)methyl
Cyano
2-(morpholin-4-yl)-ethyl
Cyano
4-(oxazol-5yl)-phenyl
Cyano
Pyridin-3-yl
Cyano
4-(cyano)-phenyl
Cyano
4-(trifluoromethoxy)-phenyl
Cyano
4-(piperidinosulfonyl)-phenyl
Cyano
4-(1H-pyrazol-1-yl)phenyl
H
3,4-(dimethoxy)-phenyl
Methyl
3,4-(dimethoxy)-phenyl
Cyano
2,3,4-(trimethoxy)-phenyl
Cyano
Cycloheptyl;
(iv) a compound of formula 1c,
wherein R 3 is selected from the group consisting of:
Ethyl;
6-fluoro-4H-benzo[d][1,3]dioxin-8-yl;
3-(cylopentyloxy)-4-(methoxy)-phenyl;
4-(heptyloxy)-phenyl;
3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl;
4-(butoxy)-phenyl; and
3,4-(dimethoxy)-phenyl;
(v) a compound of formula 1d,
wherein the position on the ring is selected from the group consisting of 2, 3, and 4;
(vi) a compound of formula 1e,
wherein R 4 and R 5 selected from the group consisting of:
R 4
R 5
H
Methyl
Methyl
H
Methyl
Methyl
—CH 2 —CH 2 —;
(vii) a compound of formula 1f,
wherein R 6 is selected from the group consisting of hydrogen, chloro, and methoxy;
(viii) a compound of formula 1g,
wherein R 7 , R 8 and R 9 are selected from the group consisting of:
R 7
R 8
R 9
Phenyl
H
H
Thiophen-2-yl
H
H
Phenyl
Methyl
H
Phenyl
H
Methyl
Phenyl
H
Ethyl
Phenyl
H
Phenyl
3,4-(dimethoxy)-
H
H
Phenyl
3,4-(dimethoxy)-
Methyl
Methyl
Phenyl
4-(chloro)-phenyl
—CH 2 —CH 2 —CH 2 —
4-(chloro)-phenyl
—CH 2 —C 2 H 4 —CH 2 —
4-(methoxy)-phenyl
—CH 2 —C 3 H 6 —CH 2 —
4-(methoxy)-phenyl
—CH 2 —CH 2 —
3,4-(dimethoxy)-
—CH 2 —CH 2 —
Phenyl
3,4,5-(trimethoxy)-
—CH 2 —CH 2 —
Phenyl
2,3,4-(trimethoxy)-
—CH 2 —CH 2 —
Phenyl
2-(methoxy)-phenyl
—CH 2 —CH 2 —
3-(methoxy)-phenyl
—CH 2 —CH 2 —
2,3-(dimethoxy)-
—CH 2 —CH 2 —
Phenyl
3,5-(dimethoxy)-
—CH 2 —CH 2 —
Phenyl
2,5-(dimethoxy)-
—CH 2 —CH 2 —
Phenyl;
(ix) a compound of formula 1h,
wherein n is defined as 3, 4, or 5;
(x) a compound of formula 1i,
wherein m is defined as 2 or 4; and
(xi) a compound selected from the group consisting of:
7. The method of claim 1 , wherein said QC-inhibitor is 1-(3-(1H-imidazole-1-yl)propyl)-3-(3,4-dimethoxy-phenyl)thiourea hydrochloride.
8. A method of prophylactically treating Alzheimer's disease in a mammal comprising:
administering to a mammalian subject a pharmaceutical composition for parenteral, enteral or oral administration comprising at least one inhibitor of glutaminyl cyclase (QC), or a pharmaceutically acceptable salt, solvate, stereoisomer or polymorph thereof, for specifically inhibiting conversion of N-terminal glutamic acid or glutamine residues to pyroglutamyl residues in at least one QC-substrate;
wherein,
the QC-inhibitor is a selective competitive QC-inhibitor; and
said competitive QC-inhibitor inhibits glutaminyl cyclase with a K i of 10 μM or less.
9. The method according to claim 8 wherein the at least one QC-substrate is selected from the group consisting of Aβ(3-40), Aβ(3-42), [Gln3]Aβ(3-40), [Gln3]Aβ(3-42), [Glu11]Aβ(11-40), [Glu11]Aβ(11-42), [Gln11]Aβ(11-40), [Gln11]Aβ(11-42), ABri, ADan, [Gln 1 ]Gastrins (17 and 34), [Gln 1 ]Neurotensin, [Gln 1 ]FPP, [Gln 1 ]TRH, [Gln 1 ]GnRH, [Gln 1 ]CCL 2, [Gln 1 ]CCL 7, [Gln 1 ]CCL 8, [Gln 1 ]CCL 13, [Gln 1 ]CCL 16, [Gln 1 ]CCL 18, [Gln 1 ]ELA, [Gln 1 ]Fractalkine, [Gln 1 ]Orexin A, [Gln 3 ]glucagon(3-29) and [Gln 5 ]substance P(5-11).
10. The method according to claim 8 wherein the pharmaceutical composition further comprises at least one additional agent selected from the group consisting of a beta-amyloid antibody, cysteine protease inhibitor, PEP-inhibitor, LiCl, acetylcholinesterase (AChE) inhibitor, PIMT enhancer, beta secretase inhibitor, gamma secretase inhibitor, aminopeptidase inhibitor, dipeptidyl peptidase inhibitor, neutral endopeptidase inhibitor, Phosphodiesterase-4 (PDE-4) inhibitor, TNFalpha inhibitor, muscarinic M1 receptor antagonist, NMDA receptor antagonist, sigma-1 receptor inhibitor, histamine H3 antagonist, immunomodulatory agent, immunosuppressive agent, MCP-1 antagonist, antegren (natalizumab), Neurelan (fampridine-SR), campath (alemtuzumab), IR 208, NBI 5788/MSP 771 (tiplimotide), paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD 271, adapalene), BAY 361677 (interleukin-4), matrix-metalloproteinase-inhibitors (e.g. BB 76163), interferon-tau (trophoblastin) and SAIK-MS.
11. The method according to claim 8 wherein the at least one inhibitor of glutaminyl cyclase (QC), or a pharmaceutically acceptable salt, solvate, stereoisomer or polymorph thereof, is selected from the group consisting of:
(i) a compound of formula 1*:
(ii) a compound of formula 1a,
wherein R is selected from the group consisting of:
Methyl;
tert-Butyl;
Benzyl;
Phenyl;
4-(fluoro)-phenyl;
4-(chloro)-phenyl;
4-(ethyl)-phenyl;
4-(trifluoromethyl)-phenyl;
4-(methoxy-carbonyl)-phenyl;
4-(acetyl)-phenyl;
4-(methoxy)-phenyl;
bicyclo[2.2.1]hept-5-en-2-yl;
3,4-(dimethoxy)-phenyl;
2,4-(dimethoxy)-phenyl;
3,5-(dimethoxy)-phenyl;
2-(methoxy-carbonyl)-phenyl;
4-(oxazol-5-yl)-phenyl;
4-(pyrazol-1-yl)-phenyl;
4-(isopropyl)-phenyl;
4-(piperidine-1-sulfonyl)-phenyl;
4-(morpholin-4-yl)-phenyl;
4-(cyano)-phenyl;
2,3-dihydro-benzo[1,4]dioxin-6-yl;
benzo[1,3]dioxol-5-yl;
3,4,5(trimethoxy)-phenyl;
3-(methoxy)-phenyl;
4-(ethoxy)-phenyl;
4-(benzyloxy)-phenyl;
4-(methoxy)-benzyl;
3,4-(dimethoxy)-benzyl;
2-(methoxy-carbonyl)-thiophene-3-yl;
3-(ethoxy-carbonyl)-4,5,6,7-tetrahydrobenzo[b]thio-phene2-yl;
2-(methoxy-carbonyl)-4-(methyl)-thiophene-3-yl;
Benzo[c][1,2,5]thiazol-4-yl;
Benzo[c][1,2,5]thiazol-5-yl;
5-(methyl)-3-(phenyl)-isooxazol-4-yl;
3,5-(dimethyl)-isooxazol-4-yl;
4-(iodo)-phenyl;
4-(bromo)-phenyl;
4-(methyl)-phenyl;
Naphthalen-1-yl;
4-(nitro)-phenyl;
Butyl;
Cyclooctyl;
Furan-2-ylmethyl;
Tetrahydrofuran-2-ylmethyl;
Benzo[1,3]dioxol-5-ylmethyl;
2-(morpholin-4-yl)-ethyl;
4-(methylsulfanyl)-phenyl;
4-(dimethylamino)-phenyl;
4-(trifluoromethoxy)-phenyl;
Benzoyl; and
Pyridin-4-yl;
(iii) a compound of formula 1b,
wherein R 1 and R 2 are selected from the croup consisting of:
R 1
R 2
Cyano
Methyl
Cyano
3,4-(dimethoxy)-phenyl
Cyano
2,4-(dimethoxy)-phenyl
Cyano
3,5-(dimethoxy)-phenyl
Cyano
2,3-dihydrobenzo[b][1,4]dioxin-
7-yl
Cyano
Benzo[d][1,3]dioxol-6-yl
Cyano
3,4,5-(trimethoxy)-phenyl
Cyano
3-(methoxy)-phenyl
Cyano
4-(ethoxy)-phenyl
Cyano
4-(benzyloxy)-phenyl
Cyano
Phenyl
Cyano
4-(methoxy)-phenyl
Cyano
4-(acetyl)-phenyl
Cyano
4-(nitro)-phenyl
Cyano
Benzyl
Cyano
Naphthalen-1-yl
Cyano
4-(fluoro)-phenyl
Cyano
4-(iodo)-phenyl
Cyano
4-(bromo)-phenyl
Cyano
Cyclooctyl
Cyano
tert-butyl
Cyano
4-(methyl)-phenyl
Cyano
4-(methylthio)-phenyl
Cyano
4-(ethyl)-phenyl
Cyano
4-(dimethylamino)-phenyl
Cyano
Butyl
Cyano
Trityl
Cyano
(Benzo[d][1,3]dioxol-6yl)methyl
Cyano
(tetrahydrofuran-2yl)methyl
Cyano
4-(trifluoromethyl)-phenyl
Cyano
(furan-2-yl)methyl
Cyano
2-(morpholin-4-yl)-ethyl
Cyano
4-(oxazol-5yl)-phenyl
Cyano
Pyridin-3-yl
Cyano
4-(cyano)-phenyl
Cyano
4-(trifluoromethoxy)-phenyl
Cyano
4-(piperidinosulfonyl)-phenyl
Cyano
4-(1H-pyrazol-1-yl)phenyl
H
3,4-(dimethoxy)-phenyl
Methyl
3,4-(dimethoxy)-phenyl
Cyano
2,3,4-(trimethoxy)-phenyl
Cyano
Cycloheptyl;
(iv) a compound of formula 1c,
wherein R 3 is selected from the group consisting of:
ethyl;
6-fluoro-4H-benzo[d][1,3]dioxin-8-yl;
3-(cylopentyloxy)-4-(methoxy)-phenyl;
4-(heptyloxy)-phenyl;
3,4-dihydro-2H-benzo[b]
[1,4]dioxepin-7-yl;
4-(butoxy)-phenyl; and
3,4-(dimethoxy)-phenyl;
(v) a compound of formula 1d,
wherein the position on the ring is selected from the group consisting of 2, 3, and 4;
(vi) a compound of formula 1e,
wherein R 4 and R 5 selected from the group consisting of:
R 4
R 5
H
Methyl
Methyl
H
Methyl
Methyl
—CH 2 —CH 2 —;
(vii) a compound of formula 1f,
wherein R 6 is selected from the group consisting of H, chloro, and methoxy;
(viii) a compound of formula 1g,
wherein R 7 , R 8 and R 9 are selected from the group consisting of:
R 7
R 8
R 9
Phenyl
H
H
Thiophen-2-yl
H
H
Phenyl
Methyl
H
Phenyl
H
Methyl
Phenyl
H
Ethyl
Phenyl
H
Phenyl
3,4-(dimethoxy)-
H
H
Phenyl
3,4-(dimethoxy)-
Methyl
Methyl
Phenyl
4-(chloro)-phenyl
—CH 2 —CH 2 —CH 2 —
4-(chloro)-phenyl
—CH 2 —C 2 H 4 —CH 2 —
4-(methoxy)-phenyl
—CH 2 —C 3 H 6 —CH 2 —
4-(methoxy)-phenyl
—CH 2 —CH 2 —
3,4-(dimethoxy)-
—CH 2 —CH 2 —
Phenyl
3,4,5-(trimethoxy)-
—CH 2 —CH 2 —
Phenyl
2,3,4-(trimethoxy)-
—CH 2 —CH 2 —
Phenyl
2-(methoxy)-phenyl
—CH 2 —CH 2 —
3-(methoxy)-phenyl
—CH 2 —CH 2 —
2,3-(dimethoxy)-
—CH 2 —CH 2 —
Phenyl
3,5-(dimethoxy)-
—CH 2 —CH 2 —
Phenyl
2,5-(dimethoxy)-
—CH 2 —CH 2 —
Phenyl;
(ix) a compound of formula 1h,
wherein n is defined as 3, 4, or 5;
(x) a compound of formula 1i,
wherein m is defined as 2 or 4; and
(xi) a compound selected from the group consisting of:
12. The method according to claim 8 wherein the at least one inhibitor of glutaminyl cyclase (QC) is 1-(3-(1H-imidazole-1-yl)propyl)-3-(3,4-dimethoxy-phenyl)thiourea hydrochloride.
13. A method of prophylactically treating progression of Alzheimer's disease in a mammal, comprising:
administering to a mammalian subject a therapeutically effective amount of at least one selective competitive inhibitor of glutaminyl cyclase (QC) for specifically inhibiting conversion of N-terminal glutamic acid or glutamine residues to pyroglutamyl residues in at least one QC-substrate,
wherein,
the QC-inhibitor has a K i of 10 μM or less, and the mammalian subject exhibits cognitive impairment characterized by loss of at least one of memory, function, language abilities, judgment or executive functioning.