- 2-Arylbenzo[ d]oxazole Phosphinate Esters as Second-Generation Modulators of Utrophin for the Treatment of Duchenne Muscular Dystrophy
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Utrophin modulation is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD), which should be applicable to all patient populations. Following on from ezutromid, the first-generation utrophin modulator, we describe the development of a second generation of utrophin modulators, based on the bioisosteric replacement of the sulfone group with a phosphinate ester and substitution of the metabolically labile naphthalene with a haloaryl substituent. The improved physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties, further reflected in the enhanced pharmacokinetic profile of the most advanced compounds, 30 and 27, led to significantly better in vivo exposure compared to ezutromid and alleviation of the dystrophic phenotype in mdx mice. While 30 was found to have dose-limiting hepatotoxicity, 27 and its enantiomers exhibited limited off-target effects, resulting in a safe profile and highlighting their potential utility as next-generation utrophin modulators suitable for progression toward a future DMD therapy.
- Babbs, Arran,Berg, Adam,Chatzopoulou, Maria,Davies, Kay E.,Davies, Stephen G.,Edwards, Benjamin,Elsey, David J.,Emer, Enrico,Guiraud, Simon,Harriman, Shawn,Lecci, Cristina,Moir, Lee,Peters, David,Robinson, Neil,Rowley, Jessica A.,Russell, Angela J.,Squire, Sarah E.,Tinsley, Jonathon M.,Wilson, Francis X.,Wynne, Graham M.
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- Anticancer supplement agent including benzo[D]oxazol derivative as effective ingredient
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Disclosed is an anticancer supplement agent including a benzo[d]oxazole derivative as an effective ingredient. The benzo[d]oxazole derivative, which is a nuclear factor E2-related factor 2 (Nrf2) inhibitor, is capable of inhibiting activity of Nrf2 that induces an antioxidant enzyme to remove reactive oxygen species (ROS) that kills a cancer cell, thereby increasing production of ROS. Therefore, the benzo[d]oxazole derivative can be used as an anticancer supplement agent that shows therapeutic effects in anticancer agent therapy or radiation therapy, and in this regard, the benzo[d]oxazole derivative can overcome tolerance of the cancer cell to anticancer agent therapy or radiation therapy and enhance apoptotic effects on the cancer cell.
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Page/Page column 11
(2016/10/17)
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- ANTICANCER SUPPLEMENT AGENT INCLUDING BENZO[D]OXAZOL DERIVATIVE AS EFFECTIVE INGREDIENT
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Disclosed is an anticancer supplement agent including a benzo[d]oxazole derivative as an effective ingredient. The benzo[d]oxazole derivative, which is a nuclear factor E2-related factor 2 (Nrf2) inhibitor, is capable of inhibiting activity of Nrf2 that induces an antioxidant enzyme to remove reactive oxygen species (ROS) that kills a cancer cell, thereby increasing production of ROS. Therefore, the benzo[d]oxazole derivative can be used as an anticancer supplement agent that shows therapeutic effects in anticancer agent therapy or radiation therapy, and in this regard, the benzo[d]oxazole derivative can overcome tolerance of the cancer cell to anticancer agent therapy or radiation therapy and enhance apoptotic effects on the cancer cell.
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Paragraph 0073; 0074; 0075
(2015/07/22)
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- BENZOXAZOLES FOR THE TREATMENT OF DUCHENNE MUSCULAR DYSTROPHY
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Compounds of formula (I), wherein R1, R2, R3, X and n are as defined herein, are useful for the treatment or prophylaxis of conditions such as Duchenne muscular dystrophy, Becker muscular dystrophy, and cachexia.
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Page/Page column 56
(2010/11/03)
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