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Last Updated: March 29, 2024

Claims for Patent: 7,732,162


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Summary for Patent: 7,732,162
Title:Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases
Abstract: 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.
Inventor(s): Hoffman; Torsten (Halle/Saale, DE), Schilling; Stephan (Halle/Saale, DE), Niestroj; Andre J. (Sennewitz, DE), Demuth; Hans-Ulrich (Haale/Saale, DE), Heiser; Ulrich (Halle/Saale, DE), Buchholz; Mirko (Halle/Saale, DE)
Assignee: Probiodrug AG (Halle (Salle), DE)
Application Number:11/685,881
Patent Claims: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 A.beta.(3-40), A.beta.(3-42), [Gln3]A.beta.(3-40), [Gln3]A.beta.(3-42), [Glu11]A.beta.(11-40), [Glu11]A.beta.(11-42), [Gln11]A.beta.(11-40), [Gln11]A.beta.(11-42), ABri, ADan, [Gln.sup.1]Gastrins (17 and 34), [Gln.sup.1]Neurotensin, [Gln.sup.1]FPP, [Gln.sup.1]TRH, [Gln.sup.1]GnRH, [Gln.sup.1]CCL 2, [Gln.sup.1]CCL 7, [Gln.sup.1]CCL 8, [Gln.sup.1]CCL 13, [Gln.sup.1]CCL 16, [Gln.sup.1]CCL 18, [Gln.sup.1]ELA, [Gln.sup.1]Fractalkine, [Gln.sup.1]Orexin A, [Gln.sup.3]glucagon(3-29) and [Gln.sup.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.sub.i of 10 .mu.M or less.

8. The method of claim 1, wherein said QC-inhibitor inhibits glutaminyl cyclase with a K.sub.i of 1 .mu.M or less.

9. The method of claim 1, wherein said QC-inhibitor inhibits glutaminyl cyclase with a K.sub.i of 0.1 .mu.M or less.

10. The method of claim 1, wherein said QC-inhibitor inhibits glutaminyl cyclase with a K.sub.i of 0.01 .mu.M or less.

11. The method of claim 1 wherein said QC-inhibitor inhibits glutaminyl cyclase with a K.sub.i of 0.001 .mu.M 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*: ##STR00035## (ii) a compound of formula 1a, ##STR00036## wherein R is selected from the group consisting of: TABLE-US-00027 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, ##STR00037## wherein R.sup.1 and R.sup.2 are selected from the group consisting of: TABLE-US-00028 R.sup.1 R.sup.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, ##STR00038## wherein R.sup.3 is selected from the group consisting of: TABLE-US-00029 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, ##STR00039## wherein the position on the ring is selected from the group consisting of 2, 3, and 4; (vi) a compound of formula 1e, ##STR00040## wherein R.sup.4 and R.sup.5 selected from the group consisting of: TABLE-US-00030 R.sup.4 R.sup.5 H Methyl Methyl H Methyl Methyl --CH.sub.2--CH.sub.2--;

(vii) a compound of formula 1f, ##STR00041## wherein R.sup.6 is selected from the group consisting of: H; Chloro; and Methoxy; (viii) a compound of formula 1g, ##STR00042## wherein R.sup.7, R.sup.8 and R.sup.9 are selected from the group consisting of: TABLE-US-00031 R.sup.7 R.sup.8 R.sup.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.sub.2--CH.sub.2--CH.sub.2-- 4-(chloro)-phenyl --CH.sub.2--C.sub.2H.sub.4--CH.sub.2-- 4-(methoxy)-phenyl --CH.sub.2--C.sub.3H.sub.6--CH.sub.2-- 4-(methoxy)-phenyl --CH.sub.2--CH.sub.2-- 3,4-(dimethoxy)- --CH.sub.2--CH.sub.2-- Phenyl 3,4,5-(trimethoxy)- --CH.sub.2--CH.sub.2-- Phenyl 2,3,4-(trimethoxy)- --CH.sub.2--CH.sub.2-- Phenyl 2-(methoxy)-phenyl- --CH.sub.2--CH.sub.2-- 3-(methoxy)-phenyl- --CH.sub.2--CH.sub.2-- 2,3-(dimethoxy)- --CH.sub.2--CH.sub.2-- Phenyl 3,5-(dimethoxy)- --CH.sub.2--CH.sub.2-- Phenyl 2,5-(dimethoxy)- --CH.sub.2--CH.sub.2-- Phenyl;

(ix) a compound of formula 1h, ##STR00043## wherein n is defined as 3, 4, or 5; (x) a compound of formula 1i, ##STR00044## wherein m is defined as 2 or 4; (xi) a compound selected from the group consisting of: ##STR00045##

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 A.beta.(3-40), A.beta.(3-42), [Gln3]A.beta.(3-40), [Gln3]A.beta.(3-42), [Glu11]A.beta.(11-40), [Glu 11]A.beta.(11-42), [Gln11]A.beta.(11-40), [Gln11]A.beta.(11-42), ABri, ADan, [Gln1]Gastrins (17 and 34), [Gln.sup.1]Neurotensin, [Gln.sup.1]FPP, [Gln.sup.1]TRH, [Gln.sup.1]GnRH, [Gln.sup.1]CCL 2, [Gln.sup.1]CCL 7, [Gln.sup.1]CCL 8, [Gln.sup.1]CCL 13, [Gln.sup.1]CCL 16, [Gln.sup.1]CCL 18, [Gln.sup.1]ELA, [Gln.sup.1]Fractalkine, [Gln.sup.1]Orexin A, [Gln.sup.3]glucagon(3-29) and [Gln.sup.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*: ##STR00046## (ii) a compound of formula 1a, ##STR00047## wherein R is selected from the group consisting of: TABLE-US-00032 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, ##STR00048## wherein R.sup.1 and R.sup.2 are selected from the group consisting of: TABLE-US-00033 R.sup.1 R.sup.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, ##STR00049## wherein R.sup.3 is selected from the group consisting of: TABLE-US-00034 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, ##STR00050## wherein the position on the ring is selected from the group consisting of 2, 3, and 4; (vi) a compound of formula 1e, ##STR00051## wherein R.sup.4 and R.sup.5 selected from the group consisting of: TABLE-US-00035 R.sup.4 R.sup.5 H Methyl Methyl H Methyl Methyl --CH.sub.2--CH.sub.2--;

(vii) a compound of formula if, ##STR00052## wherein R.sup.6 is selected from the group consisting of H, chloro, and methoxy; (viii) a compound of formula 1g, ##STR00053## wherein R.sup.7, R.sup.8 and R.sup.9 are selected from the group consisting of: TABLE-US-00036 R.sup.7 R.sup.8 R.sup.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.sub.2--CH.sub.2--CH.sub.2-- 4-(chloro)-phenyl --CH.sub.2--C.sub.2H.sub.4--CH.sub.2-- 4-(methoxy)-phenyl --CH.sub.2--C.sub.3H.sub.6--CH.sub.2-- 4-(methoxy)-phenyl --CH.sub.2--CH.sub.2-- 3,4-(dimethoxy)- --CH.sub.2--CH.sub.2-- Phenyl 3,4,5-(trimethoxy)- --CH.sub.2--CH.sub.2-- Phenyl 2,3,4-(trimethoxy)- --CH.sub.2--CH.sub.2-- Phenyl 2-(methoxy)-phenyl --CH.sub.2--CH.sub.2-- 3-(methoxy)-phenyl --CH.sub.2--CH.sub.2-- 2,3-(dimethoxy)- --CH.sub.2--CH.sub.2-- Phenyl 3,5-(dimethoxy)- --CH.sub.2--CH.sub.2-- Phenyl 2,5-(dimethoxy)- --CH.sub.2--CH.sub.2-- Phenyl;

(ix) a compound of formula 1h, ##STR00054## wherein n is defined as 3, 4, or 5; (x) a compound of formula II, ##STR00055## wherein m is defined as 2 or 4; and (xi) a compound selected from the group consisting of: ##STR00056##

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.

Details for Patent 7,732,162

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Jubilant Hollisterstier Llc N/A positive skin test control-histamine Injection 103891 03/13/1924 ⤷  Try a Trial 2023-05-05
Genzyme Corporation CAMPATH alemtuzumab Injection 103948 05/07/2001 ⤷  Try a Trial 2023-05-05
Genzyme Corporation LEMTRADA alemtuzumab Injection 103948 11/14/2014 ⤷  Try a Trial 2023-05-05
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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