Mayo Foundation for Medical Education and Research
대리인 / 주소
Fish & Richardson P.C.
인용정보
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51
초록
Small-molecule inhibitors of Botulinum toxin, including BoNTA, BoNTD and BoNTE are provided, as well as methods of using the inhibitors.
대표청구항▼
1. A composition comprising a compound according to Formula I: or a pharmaceutically acceptable salt thereof, wherein:T1-T9 have sp2 hybridization;T3 is N, and T1-T7 and T4-T9 are C;wherein T10 is W;each W is selected, independently, from the group consisting of H, NH2, OH, halo, alkyl, alkenyl, alk
1. A composition comprising a compound according to Formula I: or a pharmaceutically acceptable salt thereof, wherein:T1-T9 have sp2 hybridization;T3 is N, and T1-T7 and T4-T9 are C;wherein T10 is W;each W is selected, independently, from the group consisting of H, NH2, OH, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryloxy, heteroaryl, heteroalkyl, and heterocyclyl groups having from 1 to 8 C atoms, provided that when W is attached to X1, W is not present when X1 is N;each X1 is selected, independently, from N and C;X2 is S, O, or NH;G is selected from H, halo, NH2, OH, NHR, NRR, S(R), R(NH2), R, and O(R), wherein each R is independently an alkyl group having from 1 to 6 carbon atoms, when the X1 to which G is attached is C; or G is not present when the X1 to which G is attached is N;B is NHW or G when X1 to which B is attached is C; or not present when X1 to which B is attached is N;Y is C(═O)NR′OH, CO2H, imidazolyl, SO2NH2, R′SO2NH2, R′SH, or CONR′NH2, wherein R′ is H or an alkyl group having from 1 to 6 carbon atoms; andZ is selected from the group consisting of (CH2)mA, (CH2)mNH(CH2)nA, CO(CH2)mA, CO(CH2)mNH(CH2)nA, SO2(CH2)mA, and SO2(CH2)mNH(CH2)nA; wherein m and n are, independently, an integer from 2 to 14, inclusive;wherein A is selected from the group consisting of amino, imidazolyl, piperidinyl, piperazinyl, morpholinyl, E1, E2, E3, and E4: wherein W2 is selected from the group consisting of H, OH, N(R1)(R2), wherein R1 and R2 are, independently, H or alkyl having from 1 to 6 C atoms; and alkyl having from 1 to 6 C atoms. 2. The composition according to claim 1, wherein W is H, OH, NH2, or alkyl having from 1 to 4 C atoms. 3. The composition according to claim 1 or 2, wherein Y is C(═O)NHOH. 4. The composition of claim 1, wherein X2 is S. 5. The composition of claim 1, wherein Z is (CH2)mA, where m is an integer from 1 to 6. 6. The composition of claim 5, wherein A is amino. 7. The composition of claim 1, wherein G is selected from H, F, Cl, Br, NH2, aminoalkyl groups having from 1 to 4 C atoms, OH, and alkylthio and alkoxy groups having from 1 to 4 C atoms. 8. The composition according to claim 1, comprising a compound selected from: {5-[1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl]-2-phenylthiophene-3-yl}acetic acid;{5-[1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl]-2-phenylthiophene-3-yl}acetic acid hydrazide;2-{5-[1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl]-2-phenylthiophene-3-yl}-N-hydroxyacetamide;2-{5-[1-(5-Aminopentyl)-2-phenyl-1H-indole-6-carbonyl]-2-phenylthiophene-3-yl}-N-hydroxy-acetamide;2-{5-[1-(6-Aminohexyl)-2-phenyl-1H-indole-6-carbonyl]-2-phenylthiophene-3-yl}-N-hydroxyacetamide hydrochloride;2-(5-(1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl)-2-(aminopyridin-4-yl)thiophen-3-yl)-N-hydroxyacetamide;2-(5-(1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl)-2-(pyrimidin-5-yl)thiophen-3-yl)-N-hydroxyacetamide;2-(5-(1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl)-2-(2-aminopyrimidin-5-yl)thiophen-3-yl)-N-hydroxyacetamide;2-(5-(1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl)-2-(2-(methylthio)pyrimidin-5-yl)thiophen-3-yl)-N-hydroxyacetamide;2-(5-(1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl)-2-(2-methoxypyrimidin-5-yl)thiophen-3-yl)-N-hydroxyacetamide;2-(5-(1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl)-2-(pyridin-4-yl)thiophen-3-yl)-N-hydroxyacetamide;2-(5-(1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl)-2-(pyridin-3-yl)thiophen-3-yl)-N-hydroxyacetamide;2-(5-(1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl)-2-(6-fluoropyridin-3-yl)thiophen-3-yl)-N-hydroxyacetamide;2-(5-(1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl)-2-(4-ethylphenyl)-thiophen-3-yl)-N-hydroxyacetamide;2-(5-(1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl)-2-(4-methylphenyl)-thiophen-3-yl)-N-hydroxyacetamide;2-(5-(1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl)-2-(4-fluorophenyl)-thiophen-3-yl)-N-hydroxyacetamide;2-(5-(1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl)-2-(4-hydroxyphenyl)-thiophen-3-yl)-N-hydroxyacetamide; and2-(5-(1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl)-2-(3-hydroxyphenyl)-thiophen-3-yl)-N-hydroxyacetamide;or a pharmaceutically acceptable salt thereof. 9. The composition according to claim 8, wherein said compound is selected from: 2-{5-[1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl]-2-phenylthiophene-3-yl}-N-hydroxyacetamide;2-(5-(1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl)-2-(aminopyridin-4-yl)thiophen-3-yl)-N-hydroxyacetamide;2-(5-(1-(4-Aminobutyl)-2-phenyl-1 H-indole-6-carbonyl)-2-(pyrimidin-5-yl)thiophen-3-yl)-N-hydroxyacetamide;2-(5-(1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl)-2-(4-fluorophenyl)-thiophen-3-yl)-N-hydroxyacetamide; and2-(5-(1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl)-2-(3-hydroxyphenyl)-thiophen-3-yl)-N-hydroxyacetamide;or a pharmaceutically acceptable salt thereof. 10. A method of treating or ameliorating one or more symptoms associated with Botulinum toxin poisoning comprising administering a composition according to claim 1 to a mammal. 11. The method of claim 10, wherein the composition comprises 2-{5-[1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl]-2-phenylthiophene-3-yl}-N-hydroxyacetamide, or a pharmaceutically acceptable salt thereof. 12. The method of claim 10, wherein the composition comprises 2-(5-(1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl)-2-(pyrimidin-5-yl)thiophen-3-yl)-N-hydroxyacetamide, or a pharmaceutically acceptable salt thereof. 13. The method of claim 10, wherein the composition comprises 2-(5-(1-(4-Aminobutyl)-2-phenyl-1H-indole-6-carbonyl)-2-(3-hydroxyphenyl)-thiophen-3-yl)-N-hydroxyacetamide, or a pharmaceutically acceptable salt thereof. 14. The method of claim 10, wherein said Botulinum toxin is BoNTA, BoNTD or BoNTE. 15. The method of claim 10, wherein said mammal is a human. 16. The method according to claim 10, further comprising administering a trivalent equine antitoxin or penicillin G to said mammal. 17. A method for inhibiting a zinc protease activity comprising: contacting a zinc protease with a compound according to claim 1 wherein said zinc protease is from BoNTA, BoNTD or BoNTE. 18. A kit comprising a composition according to claim 1. 19. The kit of claim 18, wherein said composition is in the form of an injectable composition. 20. An article of manufacture comprising a composition according to claim 1 disposed within a pill, a tablet, a capsule, or a syringe.
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