Compounds, compositions and methods comprising oxadiazole derivatives
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IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/4245
C07D-271/06
출원번호
US-0426869
(2009-04-20)
등록번호
US-8207205
(2012-06-26)
발명자
/ 주소
Jones, Graham Peter
Doyle, Kevin James
출원인 / 주소
Institute for OneWorld Health
대리인 / 주소
Foley & Lardner LLP
인용정보
피인용 횟수 :
4인용 특허 :
55
초록▼
The present invention relates to compositions and methods for treating a disease in an animal, which disease is responsive to inhibiting of functional cystic fibrosis transmembrane conductance regulator (CFTR) polypeptide by administering to a mammal in need thereof an effective amount of a compound
The present invention relates to compositions and methods for treating a disease in an animal, which disease is responsive to inhibiting of functional cystic fibrosis transmembrane conductance regulator (CFTR) polypeptide by administering to a mammal in need thereof an effective amount of a compound defined herein (including those compounds set forth in Tables 1-2 or encompassed by formulas I-IV) or compositions thereof, thereby treating the disease. The present invention particularly, relates to a method of treating diarrhea and polycystic kidney disease.
대표청구항▼
1. A compound of formula I: wherein:X and Y are different and are either N or O;R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted
1. A compound of formula I: wherein:X and Y are different and are either N or O;R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, aryloxy and substituted aryloxy;R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; or when p is 0, R1 and R2 together with the atoms bound thereto, form a heterocycle or substituted heterocycle;R3 and R4 are each independently halo;R5 is selected from the group consisting of hydrogen and hydroxyl;R6 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; andp is 0, 1, 2, or 3;or a pharmaceutically acceptable salt, isomer, or tautomer thereof wherein said compound exhibits at least one of the following:a) an IC50 of less than 30 μM in a T84 assay to test inhibition of a CFTR channel;b) a greater than 30% inhibition at 20 μM in a Fisher rat thyroid (FRT) assay to test inhibition of a CFTR channel; orc) a greater than 35% inhibition at 50 μM in a T84 assay to test inhibition of a CFTR channel, provided that the compound does not have an IC50 greater than 30 μM. 2. The compound of claim 1, represented by formula II: wherein:R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, aryloxy and substituted aryloxy;R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; or when p is 0, R1 and R2 are taken together with the atoms bound thereto, form a heterocycle or substituted heterocycle;R3 and R4 are each independently halo;R5 is selected from the group consisting of hydrogen and hydroxyl;R6 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; andp is 0 or 1;or a pharmaceutically acceptable salt, isomer, or tautomer thereof. 3. The compound of claim 1, represented by formula III: wherein:R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, aryloxy and substituted aryloxy;R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; or when p is 0, R1 and R2 together with the atoms bound thereto, form a heterocycle or substituted heterocycle;R3 and R4 are each independently halo;R5 is selected from the group consisting of hydrogen and hydroxyl;R6 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; andp is 0or 1;or a pharmaceutically acceptable salt, isomer, or tautomer thereof. 4. The compound of claim 1, wherein said compound exhibits an IC50 of less than 30 μM in the T84 assay to test inhibition of a CFTR channel. 5. The compound of claim 1, wherein said compound exhibits a greater than 30% inhibition at 20 μM in the Fisher rat thyroid (FRT) assay to test inhibition of a CFTR channel. 6. The compound of claim 1, wherein said compound exhibits a greater than 35% inhibition at 50 μM in a T84 assay to test inhibition of a CFTR channel, provided that the compound does not have an IC50 greater than 30 μM. 7. The compound of claim 1, wherein R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl. 8. The compound of claim 1, wherein R3 and R4 are independently selected from the group consisting of bromo and chloro. 9. The compound of claim 1, wherein R5 is hydrogen. 10. The compound of claim 1, wherein R6 is hydrogen. 11. The compound of claim 1, wherein R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; R3 and R4 are each independently bromo or chloro; and R5 and R6 are hydrogen. 12. The compound of claim 1, wherein p is 0 and R1 and R2 together with the atoms bound thereto, form a heterocycle or substituted heterocycle. 13. The compound of claim 12, represented by formula IV: wherein:X and Y are different and are either N or O;Z is selected from the group consisting of CH and N;R3 and R4 are each independently halo;R5 is selected from the group consisting of hydrogen and hydroxyl;R6 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; andR7 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic;or a pharmaceutically acceptable salt, isomer, or tautomer thereof. 14. The compound of claim 13, wherein R3 and R4 are bromo. 15. The compound of claim 13, wherein R5 and R6 are hydrogen. 16. The compound of claim 13, wherein Z is CH; and R7 is alkyl or substituted alkyl. 17. The compound of claim 13, wherein Z is CH; R7 is alkyl or substituted alkyl; and R5 and R6 are hydrogen. 18. The compound of claim 13, wherein Z is N; R7 is aryl or substituted aryl; and R5 and R6 are hydrogen. 19. The compound of claim 18, wherein R7 is substituted phenyl. 20. A compound selected from the group consisting of: 3-(3,5-dibromo-4-hydroxyphenyl)-N-(3,3-dimethyl-2-oxobutyl)-N-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dibromo-4-hydroxyphenyl)-N-(pyridin-3-ylmethyl)-N-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dibromo-4-hydroxyphenyl)-N-methyl-N-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxamide;N-benzhydryl-3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(4-phenoxybenzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dibromo-4-hydroxyphenyl)-N-(2,2-diphenylethyl)-1,2,4-oxadiazole-5-carboxamide;N-(benzo[b]thiophen-5-ylmethyl)-3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dibromo-4-hydroxyphenyl)-N-methyl-N-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dibromo-4-hydroxyphenyl)-N-(3-(trifluoromethoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dibromo-4-hydroxyphenyl)-N-(4-phenoxybenzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dibromo-4-hydroxyphenyl)-N-(3,3-diphenylpropyl)-1,2,4-oxadiazole-5-carboxamide;N-benzhydryl-3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;N-(3,5-bis(trifluoromethyl)benzyl)-3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dibromo-4-hydroxyphenyl)-N,N-bis(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dibromo-4-hydroxyphenyl)-N-(3,4-dichlorobenzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dibromo-4-hydroxyphenyl)-N-(3-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dibromo-4-hydroxyphenyl)-N-(3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dibromo-4-hydroxyphenyl)-N-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;N-benzyl-3-(3,5-dibromo-4-hydroxyphenyl)-N-methyl-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dibromo-4-hydroxyphenyl)-N-(4-(trifluoromethoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide;N-(4-chloro-3-(trifluoromethyl)benzyl)-3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;N-benzyl-3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dibromo-4-hydroxyphenyl)-N-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dibromo-4-hydroxyphenyl)-N-(2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dibromo-4-hydroxyphenyl)-N-(2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dibromo-4-hydroxyphenyl)-N-(4-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dibromo-4-hydroxyphenyl)-N-methyl-N-(3-(trifluoromethoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide;N-(4-chlorobenzyl)-3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;N-allyl-3-(3,5-dibromo-4-hydroxyphenyl)-N-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dibromo-4-hydroxyphenyl)-N-ethyl-N-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;N-benzyl-3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-1,2,4-oxadiazole-5-carboxamide;5-(3,5-dibromo-4-hydroxyphenyl)-N-(3-(trifluoromethoxy)benzyl)-1,2,4-oxadiazole-3-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(3-(trifluoromethoxy)benzyl)-1,2,4-oxadiazole-3-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(4-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide;N-benzyl-5-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-1,2,4-oxadiazole-3-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(4-phenoxybenzyl)-1,2,4-oxadiazole-3-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(3,4-difluorobenzyl)-1,2,4-oxadiazole-3-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(4-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide;N-(2-chlorobenzyl)-5-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxamide;N-(4-chlorobenzyl)-5-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-1,2,4-oxadiazole-3-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(3,5-dichlorobenzyl)-1,2,4-oxadiazole-3-carboxamide;N-(3-chlorobenzyl)-5-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-N-(4-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(pyridin-3-ylmethyl)-N-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(2-oxo-2-phenylethyl)-N-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(3,3-dimethyl-2-oxobutyl)-N-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;N-(but-2-ynyl)-3-(3,5-dichloro-4-hydroxyphenyl)-N-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N,N-bis(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(2,3-difluorobenzyl)-1,2,4-oxadiazole-3-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(2,6-difluorobenzyl)-1,2,4-oxadiazole-3-carboxamide;(4-(4-chloro-3-(trifluoromethyl)phenyl)piperazin-1-yl)(3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone;(3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methanone;(3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methanone;(3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)(4-phenylpiperazin-1-yl)methanone;(4-benzylpiperidin-1-yl)(3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone;(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)(3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone;(4-(4-tert-butylphenyl)piperazin-1-yl)(3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone;(3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)(4-(2-methoxyphenyl)piperazin-1-yl)methanone;(3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)(4-(2,4-difluorophenyl)piperazin-1-yl)methanone;(3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)(4-(3-fluorophenyl)piperazin-1-yl)methanone;2-(4-(5-(4-benzylpiperidine-1-carbonyl)-1,2,4-oxadiazol-3-yl)-2,6-dibromophenoxy)acetic acid;(4-benzylpiperidin-1-yl)(5-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;methyl 1-(2-(4-(5-(4-benzylpiperidine-1-carbonyl)-1,2,4-oxadiazol-3-yl)-2,6-dibromophenoxy)acetyl)piperidine-4-carboxylate;2-(4-(5-(4-benzylpiperidine-1-carbonyl)-1,2,4-oxadiazol-3-yl)-2,6-dibromophenoxy)-N,N-bis(2-hydroxyethyl)acetamide;(4-benzylpiperidin-1-yl)(5-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; and1-(4-(3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carbonyl)piperazin-1-yl)-2,2-dimethylpropan-1-one;or a pharmaceutically acceptable salt, isomer, or tautomer thereof. 21. A compound selected from the group consisting of: 3-(3,5-dibromo-4-hydroxyphenyl)-N-(4-phenoxyphenyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dibromo-4-hydroxyphenyl)-N-(3,3-dimethylbutyl)-1,2,4-oxadiazole-5-carboxamide;2-(2,6-dichloro-4-(3-(methyl(3-(trifluoromethyl)benzyl)carbamoyl)-1,2,4-oxadiazol-5-yl)phenoxy)acetic acid;2-(2,6-dichloro-4-(3-(4-phenoxybenzylcarbamoyl)-1,2,4-oxadiazol-5-yl)phenoxy)acetic acid;3-(3,5-dichloro-4-hydroxyphenyl)-N-propyl-N-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(prop-2-ynyl)-N-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(2-ethoxyethyl)-N-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(2-(2-methoxyethoxy)ethyl)-N-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(3,5-difluorobenzyl)-1,2,4-oxadiazole-3-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(2,5-difluorobenzyl)-1,2,4-oxadiazole-3-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(2,4-difluorobenzyl)-1,2,4-oxadiazole-3-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(4-fluorobenzyl)-1,2,4-oxadiazole-3-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(3-fluorobenzyl)-1,2,4-oxadiazole-3-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(3,4-difluorobenzyl)-N-methyl-1,2,4-oxadiazole-3-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(3,4,5-trifluorobenzyl)-1,2,4-oxadiazole-3-carboxamide;N-benzyl-N-(2-(benzylamino)ethyl)-5-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxamide;5-(3,5-dichloro-2,4-dihydroxyphenyl)-N-(3-(trifluoromethoxy)benzyl)-1,2,4-oxadiazole-3-carboxamide;N-benzyl-3-(3,5-dichloro-4-hydroxyphenyl)-N-(2-hydroxyethyl)-1,2,4-oxadiazole-5-carboxamide;N-benzyl-3-(3,5-dibromo-4-hydroxyphenyl)-N-(2-hydroxyethyl)-1,2,4-oxadiazole-5-carboxamide;N-(4-chloro-3-fluorobenzyl)-3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;N-(biphenyl-3-ylmethyl)-3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(2-fluoro-5-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(4-isopropoxybenzyl)-1,2,4-oxadiazole-5-carboxamide;N-(4-chlorobenzyl)-3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;N-(3-chloro-4-fluorobenzyl)-3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;N-(biphenyl-4-ylmethyl)-3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(2,4-difluorobenzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(4-(dimethylamino)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(3-(difluoromethoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide;N-(4-tert-butylbenzyl)-3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(3,5-difluorobenzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-N-(4-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-N-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;N-benzyl-3-(3,5-dichloro-4-hydroxyphenyl)-N-ethyl-1,2,4-oxadiazole-5-carboxamide;N-(3-(benzyloxy)benzyl)-3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-N-(4-phenoxybenzyl)-1,2,4-oxadiazole-5-carboxamide;N-(1-(4-bromophenyl)ethyl)-3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-N-(3-phenoxybenzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(3-phenoxybenzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(4-fluoro-3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(3-(pyrimidin-2-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide;N-(4-tert-butylbenzyl)-3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-1,2,4-oxadiazole-5-carboxamide;N-(1-(4-chlorophenyl)ethyl)-3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(4-ethylbenzyl)-N-methyl-1,2,4-oxadiazole-5-carboxamide;N-benzyl-3-(3,5-dichloro-4-hydroxyphenyl)-N-(3,3-dimethyl-2-oxobutyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(3,4-difluorobenzyl)-N-(3,3-dimethyl-2-oxobutyl)-1,2,4-oxadiazole-5-carboxamide;N-(4-(benzyloxy)benzyl)-3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(3-fluoro-5-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(2-fluoro-5-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide;N-(4-((1H-pyrazol-1-yl)methyl)benzyl)-5-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(3-(piperidin-1-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(4-(dimethylamino)benzyl)-1,2,4-oxadiazole-3-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(4-fluoro-3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(3-(dimethylamino)benzyl)-1,2,4-oxadiazole-3-carboxamide;N-(3-(1H-pyrazol-1-yl)benzyl)-5-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N,N-bis(pyridin-3-ylmethyl)-1,2,4-oxadiazole-5-carboxamide;5-(3,5-dichloro-4-hydroxyphenyl)-N-(3-(difluoromethoxy)benzyl)-1,2,4-oxadiazole-3-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(3,3-dimethyl-2-oxobutyl)-N-(3-(trifluoromethoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(3,3-dimethyl-2-oxobutyl)-N-(4-phenoxybenzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(4-(piperidin-1-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide;N-benzyl-3-(3,5-dichloro-4-hydroxyphenyl)-N-(pyridin-3-ylmethyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(4-phenoxybenzyl)-N-(pyridin-3-ylmethyl)-1,2,4-oxadiazole-5-carboxamide;N-allyl-3-(3,5-dichloro-4-hydroxyphenyl)-N-(3-(trifluoromethoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide;N-allyl-3-(3,5-dichloro-4-hydroxyphenyl)-N-(3,4-difluorobenzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(4-(4-fluorophenoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-N-(3-(6-methylpyrazin-2-yloxy)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-N-(4-(pyridin-2-yloxy)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-N-(4-(5-(trifluoromethyl)pyridin-2-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-N-(3-(pyridin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-N-(3-(pyrimidin-2-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-N-(3-(pyrimidin-5-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-N-(3-(pyridin-2-yloxy)benzyl)-1,2,4-oxadiazole-5-carboxamide;N-(4-(3-chlorophenoxy)benzyl)-3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;N-(4-(3-chloro-4-isopropoxyphenoxy)benzyl)-3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(4-(4-(trifluoromethoxy)phenoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide;N-(4-(4-bromophenoxy)benzyl)-3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(4-(3-fluoro-4-methoxyphenoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide;N-(4-(3-chloro-4-ethoxyphenoxy)benzyl)-3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-N-(3-(pyridin-3-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-N-(4-(pyridin-2-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-N-(4-morpholinobenzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-N-(4-(pyrimidin-5-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-N-(4-(pyrimidin-2-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(4-(3-(trifluoromethoxy)phenoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(4-(4-fluoro-3-methoxyphenoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide;N-(4-(4-tert-butylphenoxy)benzyl)-3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;N-(4-(3-chloro-4-methylphenoxy)benzyl)-3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(4-(3-fluorophenoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide;N-(4-(3-chloro-4-methoxyphenoxy)benzyl)-3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(4-(3,5-dichlorophenoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(4-(4-(dimethylamino)phenoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(4-(4-(trifluoromethyl)phenoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(4-(3-(dimethylamino)phenoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(4-(4-fluoro-3-(trifluoromethyl)phenoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide;N-(4-(3-bromo-5-fluorophenoxy)benzyl)-3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;N-(4-(4-chloro-3-(trifluoromethyl)phenoxy)benzyl)-3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxamide;(3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)(4-(hydroxydiphenylmethyl)piperidin-1-yl)methanone;(4-benzylpiperidin-1-yl)(3-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone; and2-(4-(5-(4-benzylpiperidine-1-carbonyl)-1,2,4-oxadiazol-3-yl)-2,6-dibromophenoxy)-N-tert-butoxyacetamide;or a pharmaceutically acceptable salt, isomer, or tautomer thereof. 22. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 23. A method for treating diarrhea in an animal in need thereof comprising administering to the animal an effective amount of the composition of claim 22, thereby treating diarrhea. 24. The method of claim 23, wherein the composition is administered in a pharmaceutical formulation suitable for administration administration orally, intraluminely or by suppository. 25. The method of claim 24, wherein the pharmaceutical formulation is a sustained release formulation. 26. The method of claim 23, wherein the animal is a human patient or a farm animal. 27. The method of claim 23, wherein the diarrhea is secretory diarrhea. 28. The method of claim 23, wherein the diarrhea is selected from the group consisting of infectious diarrhea, inflammatory diarrhea and diarrhea associated with chemotherapy. 29. The method of claim 23, further comprising administering an effective amount of an oral glucose-electrolyte solution or an effective amount of a micronutrient to the animal. 30. A method for treating polycystic kidney disease (PKD) in an animal in need thereof, comprising administering to the animal an effective amount of the composition of claim 22, thereby treating PKD. 31. A method of treating a disease in an animal, wherein the disease is selected from the group consisting of secretory diarrhea, inflammatory diarrhea, inflammatory bowel disease, infectious diarrhea, polycystic kidney disease (PKD), cardiac arrhythmia, male infertility and disorders associated with neovascularization, comprising administering to the animal in need thereof an effective amount of the composition of claim 22, thereby treating the disease. 32. A method for inhibiting the transport of a halide ion across a mammalian cell membrane expressing functional cystic fibrosis transmembrane conductance regulator (CFTR) polypeptide, comprising contacting the CFTR polypeptide with an effective amount of the composition of claim 22, thereby inhibiting the transport of the halide ion. 33. The method of claim 32, wherein the halide ion is at least one of F−, Cl− or Br−. 34. The method of claim 32, wherein the halide ion is Cl−. 35. The method of claim 32, wherein the functional CFTR is wild-type full length CFTR. 36. The method of claim 32, wherein the mammalian cell is an epithelial cell, luminal epithelial cell or a kidney cell. 37. The method of claim 36, wherein the mammalian cell is an intestinal epithelial cell or a colon epithelial cell. 38. A compound represented by formula II: wherein:R1 is aryl substituted with an optionally substituted aryloxy;R2 is hydrogen, alkyl, or substituted alkyl;R3 and R4 are each independently halo;R5 is hydrogen;R6 is hydrogen or substituted alkyl; andp is 1;or a pharmaceutically acceptable salt or tautomer thereofwherein said compound exhibits at least one of the following:a) an IC50 of less than 30 μM in a T84 assay to test inhibition of a CFTR channel;b) a greater than 30% inhibition at 20 μM in a Fisher rat thyroid (FRT) assay to test inhibition of a CFTR channel; orc) a greater than 35% inhibition at 50 μM in a T84 assay to test inhibition of a CFTR channel, provided that the compound does not have an IC50 greater than 30 μM. 39. The compound of claim 38, wherein R1 is phenyl substituted with an optionally substituted aryloxy. 40. The compound of claim 38, wherein R1 is phenyl substituted with a phenoxy group. 41. The compound of claim 38, wherein R1 is phenyl substituted with a substituted phenoxy group, which phenoxy group is substituted with 1 or 2 substituents selected from halo, amino, substituted amino, C1-C3 alkoxy, substituted C1-C3 alkoxy, C1-C3 alkyl, and substituted C1-C3 alkyl. 42. The compound of claim 38, wherein R2 is hydrogen. 43. The compound of claim 38, wherein R3 and R4 are each independently chloro or bromo. 44. The compound of claim 38, wherein R3 and R4 are bromo. 45. The compound of claim 38, wherein R3 and R4 are chloro. 46. The compound of claim 38, wherein R6 is hydrogen. 47. The compound of claim 38, wherein R6 is substituted alkyl. 48. The compound of claim 38, wherein R1 is phenyl substituted with a phenoxy group or is phenyl substituted with a substituted phenoxy group, which substituted phenoxy group is substituted with 1 or 2 substituents selected from halo, amino, substituted amino, C1-C3 alkoxy, substituted C1-C3 alkoxy, C1-C3 alkyl, and substituted C1-C3 alkyl;R2 is hydrogen;R3 and R4 are each independently chloro or bromo; andR6 is hydrogen or substituted alkyl. 49. The compound of claim 38, wherein R1 is phenyl substituted with a phenoxy group;R2 is hydrogen;R3 and R4 are each independently chloro or bromo; andR6 is hydrogen. 50. A monophosphate derivative of the compound of claim 49 or a pharmaceutically acceptable salt thereof, wherein the phenolic hydroxy group of the compound of claim 49 is converted to a monophosphate. 51. A compound of formula: or a pharmaceutically acceptable salt thereof. 52. A monophosphate derivative of the compound of claim 51 or a pharmaceutically acceptable salt thereof, wherein the phenolic hydroxy group of the compound of claim 51 is converted to a monophosphate. 53. A pharmaceutical composition comprising the compound of claim 38 and one or more pharmaceutically acceptable excipients. 54. A pharmaceutical composition comprising the compound of claim 48 and one or more pharmaceutically acceptable excipients. 55. A pharmaceutical composition comprising the compound of claim 51 and one or more pharmaceutically acceptable excipients. 56. A pharmaceutical composition comprising the compound of claim 52 and one or more pharmaceutically acceptable excipients. 57. A method for treating diarrhea in an animal in need thereof comprising administering to the animal an effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof: wherein: R1 is aryl substituted with an optionally substituted aryloxy;R2 is hydrogen, alkyl, or substituted alkyl;R3 and R4 are each independently halo;R5 is hydrogen;R6 is hydrogen or substituted alkyl; andp is 1;or a pharmaceutically acceptable salt or tautomer thereofwherein said compound exhibits at least one of the following:a) an IC50 of less than 30 μM in a T84 assay to test inhibition of a CFTR channel;b) a greater than 30% inhibition at 20 μM in a Fisher rat thyroid (FRT) assay to test inhibition of a CFTR channel; orc) a greater than 35% inhibition at 50 μM in a T84 assay to test inhibition of a CFTR channel, provided that the compound does not have an IC50 greater than 30 μM. 58. A method for treating diarrhea in an animal in need thereof comprising administering to the animal an effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof: wherein:R1 is phenyl substituted with a phenoxy group or is phenyl substituted with a substituted phenoxy group, which substituted phenoxy group is substituted with 1 or 2 substituents selected from halo, amino, substituted amino, C1-C3 alkoxy, substituted C1-C3 alkoxy, C1-C3 alkyl, and substituted C1-C3 alkyl;R2 is hydrogen;R3 and R4 are each independently chloro or bromo;R5 is hydrogen; andR6 is hydrogen or substituted alkylwherein said compound exhibits at least one of the following:a) an IC50 of less than 30 μM in a T84 assay to test inhibition of a CFTR channel;b) a greater than 30% inhibition at 20 μM in a Fisher rat thyroid (FRT) assay to test inhibition of a CFTR channel; orc) a greater than 35% inhibition at 50 μM in a T84 assay to test inhibition of a CFTR channel, provided that the compound does not have an IC50 greater than 30 μM. 59. The method of claim 58, wherein the diarrhea is secretory diarrhea, infectious diarrhea, inflammatory diarrhea, or diarrhea associated with chemotherapy. 60. The method of claim 58, wherein the compound is administered orally, intraluminely, or by suppository. 61. The method of claim 58, wherein the animal is human or a farm animal. 62. A method for treating diarrhea in an animal in need thereof comprising administering to the animal an effective amount of a compound of formula: or a pharmaceutically acceptable salt thereof. 63. The method of claim 62, wherein the diarrhea is secretory diarrhea, infectious diarrhea, inflammatory diarrhea, or diarrhea associated with chemotherapy. 64. The method of claim 62, wherein the compound is administered orally, intraluminely, or by suppository. 65. The method of claim 62, wherein the animal is human or a farm animal. 66. A method for treating diarrhea in an animal in need thereof comprising administering to the animal an effective amount of a monophosphate derivative of a compound of formula: or a pharmaceutically acceptable salt thereof, wherein the phenolic hydroxy group of the compound of formula: is converted to the monophosphate derivative. 67. The method of claim 66, wherein the diarrhea is secretory diarrhea, infectious diarrhea, inflammatory diarrhea, or diarrhea associated with chemotherapy. 68. The method of claim 66, wherein the compound is administered orally, intraluminely, or by suppository. 69. The method of claim 66, wherein the animal is human or a farm animal.
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