- Discovery of the Oxadiazine FRM-024: A Potent CNS-Penetrant Gamma Secretase Modulator
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The recent approval of aducanumab for Alzheimer's disease has heightened the interest in therapies targeting the amyloid hypothesis. Our research has focused on identification of novel compounds to improve amyloid processing by modulating gamma secretase activity, thereby addressing a significant biological deficit known to plague the familial form of the disease. Herein, we describe the design, synthesis, and optimization of new gamma secretase modulators (GSMs) based on previously reported oxadiazine 1. Potency improvements with a focus on predicted and measured properties afforded high-quality compounds further differentiated via robust Aβ42 reductions in both rodents and nonhuman primates. Extensive preclinical profiling, efficacy studies, and safety studies resulted in the nomination of FRM-024, (+)-cis-5-(4-chlorophenyl)-6-cyclopropyl-3-(6-methoxy-5-(4-methyl-1H-imidazole-1-yl)pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine, as a GSM preclinical candidate for familial Alzheimer's disease.
- Acharya, Raksha,Blain, Jean-Fran?ois,Burnett, Duane A.,Bursavich, Matthew G.,Costa, Donald E.,Freeman, Emily A.,Harrison, Bryce A.,Hrdlicka, Lori A.,Jin, Hong,Kapadnis, Sudarshan,Koenig, Gerhard,Moffit, Jeffrey S.,Murphy, Deirdre,Nolan, Scott J.,Patzke, Holger,Tang, Cuyue,Van Voorhies, Hilliary E.,Wen, Melody
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p. 14426 - 14447
(2021/10/12)
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- Access to α-Cyano Carbonyls Bearing a Quaternary Carbon Center by Reductive Cyanation
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Reductive cyanation of tertiary alkyl bromides using electrophilic cyanating reagent and zinc reductant was developed, providing various α-cyano ketones, esters, and carboxamides containing a nitrile-bearing all-carbon quaternary center in good to excellent yields under mild reaction conditions. The corresponding reaction mechanism involving in situ generated organozinc reagent and reactivity distinction was elucidated by density functional theory computation.
- Ren, Xinyi,Shen, Chaoren,Wang, Guangzhu,Shi, Zhanglin,Tian, Xinxin,Dong, Kaiwu
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supporting information
p. 2527 - 2532
(2021/05/05)
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- OXADIAZINE COMPOUNDS AND METHODS OF USE THEREOF
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The present disclosure relates to oxadiazine compounds, pharmaceutical compositions comprising an effective amount of an oxadiazine compound and methods for using an oxadiazine compound in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of an oxadiazine compound.
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Paragraph 0330
(2017/03/14)
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- Discovery of 6-phenylpyrimido[4,5- B ][1,4]oxazines as potent and selective Acyl CoA: Diacylglycerol acyltransferase 1 (DGAT1) inhibitors with in vivo efficacy in rodents
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The discovery and optimization of a series of acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors based on a pyrimido[4,5-b][1,4]oxazine scaffold is described. The SAR of a moderately potent HTS hit was investigated resulting in the discovery of phenylcyclohexylacetic acid 1, which displayed good DGAT1 inhibitory activity, selectivity, and PK properties. During preclinical toxicity studies a metabolite of 1 was observed that was responsible for elevating the levels of liver enzymes ALT and AST. Subsequently, analogues were synthesized to preclude the formation of the toxic metabolite. This effort resulted in the discovery of spiroindane 42, which displayed significantly improved DGAT1 inhibition compared to 1. Spiroindane 42 was well tolerated in rodents in vivo, demonstrated efficacy in an oral triglyceride uptake study in mice, and had an acceptable safety profile in preclinical toxicity studies.
- Fox, Brian M.,Sugimoto, Kazuyuki,Iio, Kiyosei,Yoshida, Atsuhito,Zhang, Jian,Li, Kexue,Hao, Xiaolin,Labelle, Marc,Smith, Marie-Louise,Rubenstein, Steven M.,Ye, Guosen,McMinn, Dustin,Jackson, Simon,Choi, Rebekah,Shan, Bei,Ma, Ji,Miao, Shichang,Matsui, Takuya,Ogawa, Nobuya,Suzuki, Masahiro,Kobayashi, Akio,Ozeki, Hidekazu,Okuma, Chihiro,Ishii, Yukihito,Tomimoto, Daisuke,Furakawa, Noboru,Tanaka, Masahiro,Matsushita, Mutsuyoshi,Takahashi, Mitsuru,Inaba, Takashi,Sagawa, Shoichi,Kayser, Frank
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p. 3464 - 3483
(2014/05/20)
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- Substituted diazolylalkyl-carbinols, a process for their preparation and their use as antimycotic agents
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The invention relates to compounds and their derivatives, said compounds being described herein as those of Formula (I). The compounds and compositions containing them are effective antimycotic agents and the invention includes methods for the use of said compounds and compositions.
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- Antiviral agents
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The invention relates to hydroxyethylazolyl derivatives, defined herein by formula (I) and particularly to the use of said derivatives for the treatment of viral infections.
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- Substituted hydroxyalkyl-azole fungicidal agents, their preparation and their use
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A method of combating fungi which comprises to such fungi or to a fungus habitat a fungicidally effective amount of a substituted hydroxyalkyl-azole of the formula STR1 in which R1 is optionally substituted phenyl, --O-phenyl, --S-phenyl, --SO-phenyl, --SO2 -phenyl, --CH2 --phenyl, --CH2 --O-phenyl, --CH2 --S-phenyl, --CH2 --SO-phenyl or --CH2 --SO2 -phenyl, R2 is alkyl, R3 is alkyl, X is a nitrogen atom or the CH group, Y is halogen, alkyl, cycloalkyl, alkoxy, alkylthio, halogenoalkyl, halogenoalkoxy, halogenoalkylthio, optionally substituted phenyl, optionally substituted phenylalkyl or optionally substituted phenylalkoxy, and m is 0, 1, 2 or 3, or an addition product thereof with an acid or metal salt.
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- Facile Synthesis of 2-Alkoxy-2-aryloxiranes
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Tertiary α-bromoalkyl aryl ketones 1 were converted into 2-alkoxy-2-aryloxiranes 4 exclusively by reaction with excess potassium carbonate in the corresponding dry alcohol.Silver carbonate in a dry alcohol with these α-bromo ketones yielded competitively formation of 2-alkoxyoxiranes and semi-benzilic Favorskii rearrangement (-> 5), while silver hexafluoroantimonate in the same medium afforded the latter rearrangement reaction exclusively.
- Kimpe, Norbert De,Buyck, Laurent De,Verhe, Roland,Schamp, Niceas
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p. 3631 - 3636
(2007/10/02)
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