- Selective cathepsin s inhibition with MIV-247 attenuates mechanical allodynia and enhances the antiallodynic effects of gabapentin and pregabalin in a mouse model of neuropathic pain
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Cathepsin S inhibitors attenuate mechanical allodynia in preclinical neuropathic pain models. The current study evaluated the effects when combining the selective cathepsin S inhibitor MIV-247 with gabapentin or pregabalin in a mouse model of neuropathic pain. Mice were rendered neuropathic by partial sciatic nerve ligation. MIV-247, gabapentin, or pregabalin were administered alone or in combination via oral gavage. Mechanical allodynia was assessed using von Frey hairs. Neurobehavioral side effects were evaluated by assessing beamwalking. MIV-247, gabapentin, and pregabalin concentrations in various tissueswere measured. Oral administration of MIV-247 (100-200 μmol/kg) dose-dependently attenuated mechanical allodynia by up to approximately 50%reversal when given as a single dose or when given twice daily for 5 days. No behavioral deficits were observed at any dose of MIV-247 tested. Gabapentin (58-350 μmol/kg) and pregabalin (63-377 μmol/kg) also inhibited mechanical allodynia with virtually complete reversal at the highest doses tested. The minimum effective dose of MIV-247 (100 μmol/kg) in combination with the minimum effective dose of pregabalin (75 μmol/kg) or gabapentin (146 μmol/kg) resulted in enhanced antiallodynic efficacy without augmenting side effects. A subeffective dose of MIV-247 (50 μmol/kg) in combination with a subeffective dose of pregabalin (38 μmol/kg) or gabapentin (73 μmol/kg) also resulted in substantial efficacy. Plasma levels of MIV-247, gabapentin, and pregabalin were similar when given in combination as to when given alone. Cathepsin S inhibition with MIV-247 exerts significant antiallodynic efficacy alone, and also enhances the effect of gabapentin and pregabalin without increasing side effects or inducing pharmacokinetic interactions.
- Hewitt, Ellen,Pitcher, Thomas,Rizoska, Biljana,Tunblad, Karin,Henderson, Ian,Sahlberg, Britt-Louise,Grabowska, Urszula,Classon, Bj?rn,Edenius, Charlotte,Malcangio, Marzia,Lindstr?m, Erik
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- CYSTEINE PROTEASE INHIBITORS
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Compounds of the formula (I) wherein One of A1 and A2 is N-CH3 and the other is CH; R1 is C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl or oxetan-3-yl, wherein C3-C6cycloalkyl is optionally substituted with one, two or three fluoro or with CF3; R2a and R2b are independently selected from H, halo, C1-C4alkyl, C1-C4haloalkyl and C1- C4alkoxy; R3 is CH3 or F; n is 1, 2, 3 or 4; or a pharmaceutically acceptable salt, hydrate or N-oxide thereof for the use in the prophylaxis and/or treatment of a disorder characterised by inappropriate expression or activation of cathepsin S.
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Page/Page column 19
(2013/02/28)
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- CYSTEINE PROTEASE INHIBITORS
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Compounds of the formula (I) wherein R1a is H; and R1b is C1-C6alkyl, Carbocyclyl or Het; or R1a and R1b together define a saturated cyclic amine with 3-6 ring atoms; R2a and Rs
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- CYSTEINE PROTEASE INHIBITORS
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Compounds of Formula (II) wherein R1a is H; and R1b is C1-C6alkyl, Carbocyclyl or Het; or R1a and R1b together define a saturated cyclic amine with 3-6 ring atoms; R2a and R
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- NEW CATHEPSIN S PROTEASE INHIBITORS, USEFUL IN THE TREATMENT OF E.G. AUTOIMMUNE DISORDERS, ALLERGY AND CHRONIC PAIN CONDITIONS
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Compounds of the formula (I) wherein R2a and R2b are independently H, halo, C1-C4alkyl, C1-C4haloalkyl or C1-C4alkoxy, or R2a and R2b together wi
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- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
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Compounds having antibacterial activity are disclosed. The compounds have the following structure (I) including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, Q5, R1, R2, R3, Z1 and Z2 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Page/Page column 76
(2011/04/26)
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- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
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Compounds having antibacterial activity are disclosed. The compounds have the following structure (I): (Formula (I)), including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, R1, R2, R3, Z1 and Z2 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Page/Page column 81
(2011/04/26)
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- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
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Compounds having antibacterial activity are disclosed. The compounds have the following structure (I): (Formula (I)), including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, R1, R2, R3, Z1 and Z2 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Page/Page column 79
(2011/04/26)
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- TREATMENT OF URINARY TRACT INFECTIONS WITH ANTIBACTERIAL AMINOGLYCOSIDE COMPOUNDS
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A method for treating a urinary tract infection in a mammal in need thereof is disclosed, the method comprising administering to the mammal an effective amount of an antibacterial aminoglycoside compound.
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- CYSTEINE PROTEASE INHIBITORS
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Compounds of the formula I wherein R1a is H; and R1b is C1-C6 alkyl, Carbocyclyl or Het; or R1a and R1b together define a saturated cyclic amine with 3-6 ring atoms; R2a and Rsu
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Page/Page column 26; 27
(2010/08/05)
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- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
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Compounds having antibacterial activity are disclosed. The compounds have the following structure (I): (I) including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Ql, Q2, Rl, R2 and R3 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Page/Page column 67
(2010/04/28)
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- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
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Compounds having antibacterial activity are disclosed. The compounds have the following structure (I) or (II): including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, Q3, R1, R2 and R3 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Page/Page column 111
(2010/12/17)
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- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
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Compounds having antibacterial activity are disclosed. The compounds have the following structure (I): (I) including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, R1, R2 and R3 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Page/Page column 67
(2010/04/28)
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- ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
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Compounds of structure (I): having antibacterial activity are disclosed, including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, Q3, R8 and R9 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Page/Page column 188
(2009/06/27)
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- Synthesis and structure-activity relationships of 7-[3-(1- aminoalkyl)pyrrolidinyl]- and 7-[3-1-aminocycloalkyl)pyrrolidinyl]-quinolone antibacterials
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A series of 7-[3-(1-aminoalkyl and 1-aminocycloalkyl)-1- pyrrolidinyl]quinolones have been prepared and their biological properties evaluated. Among them, 1-(S)-aminoalkyl derivatives exhibited potent antibacterial activities against gram-positive and gram-negative organisms. They had moderate lipophilicity and high aqueous solubility compared to their aminomethyl counterparts; e.g., the 3-(1-aminoethyl)-1-pyrrolidinyl compound (83) showed superior pharmacokinetic properties to its aminomethyl counterpart (6).
- Kimura,Atarashi,Takahashi,Hayakawa
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p. 1442 - 1454
(2007/10/02)
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