Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases
The present invention provides novel physiological substrates of mammalian glutaminyl cyclase (QC, EC 2.3.2.5), new effectors of QC, methods for screening for such effectors, and the use of such effectors and pharmaceutical compositions comprising such effectors for the treatment of conditions that can be treated by modulation of QC-activity. Preferred compositions additionally comprise inhibitors of DP IV or DP IV-like enzymes for the treatment or alleviation of conditions that can be treated by modulation of QC- and DP IV-activity.
1. A method of treating a neurodegenerative disease in a mammal, comprising
administering to a mammalian subject a therapeutically effective amount of at least one inhibitor of glutaminyl cyclase (QC) for inhibiting conversion of N-terminal glutamic acid or glutamine residues to pyroglutamyl residues in at least one QC-substrate,
wherein said neurodegenerative disease is selected from the group consisting of mild cognitive impairment (MCI), Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, and Familial Danish Dementia.
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 said neurodegenerative disease is selected from the grow, consisting of Alzheimer's disease and mild cognitive impairment (MCI).
4. The method according to claim 1 wherein administration of the QC inhibitor results in suppression of myeloid progenitor cell proliferation.
5. The method of claim 1 , wherein said QC-inhibitor is a competitive QC-inhibitor.
6. The method of claim 1 , wherein said QC-inhibitor selectively binds to an active-site bound metal ion of QC.
7. The method of claim 1 wherein said QC-inhibitor inhibits glutaminyl cyclase with a K i of 10 μM or less.
8. The method of claim 1 , wherein said QC-inhibitor inhibits glutaminyl cyclase with a K i of 1 μM or less.
9. The method of claim 1 , wherein said QC-inhibitor inhibits glutaminyl cyclase with a K i of 0.1 μM or less.
10. The method of claim 1 , wherein said QC-inhibitor inhibits glutaminyl cyclase with a K i of 0.01 μM or less.
11. The method of claim 1 wherein said QC-inhibitor inhibits glutaminyl cyclase with a K i of 0.001 μM or less.
12. 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)-pheny;l
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-y)-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]thiophene2-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:
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;
(xi) a compound selected from the group consisting of:
13. The method of claim 1 , wherein said QC-inhibitor is 1-(3-(1H-imidazole-1-yl)propyl)-3-(3,4-dimethoxy-phenyl) thiourea hydrochloride.
14. A method of treating a neurodegenerative 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 inhibiting conversion of N-terminal glutamic acid or glutamine residues to pyroglutamyl residues in at least one QC-substrate;
wherein said neurodegenerative disease is selected from the group consisting of mild cognitive impairment (MCI), Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, and Familial Danish Dementia.
15. The method according to claim 14 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), [Glu 11]Aβ(11-42), [Gln11]Aβ(11-40), [Gln11]Aβ(11-42), ABri, ADan, [Gln1]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).
16. The method according to claim 14 wherein said neurodegenerative disease is selected from the grow, consisting of Alzheimer's disease and mild cognitive impairment (MCI).
17. The method according to claim 14 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/MS P 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.
18. The method according to claim 14 wherein the at least one inhibitor of glutaminyl cyclase (QC), 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-y)-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 if,
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 II,
wherein m is defined as 2 or 4; and
(xi) a compound selected from the group consisting of:
19. The method according to claim 14 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.