- Discovery of the Oxadiazine FRM-024: A Potent CNS-Penetrant Gamma Secretase Modulator
-
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
-
p. 14426 - 14447
(2021/10/12)
-
- OXADIAZINE COMPOUNDS AND METHODS OF USE THEREOF
-
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.
- -
-
Paragraph 0328
(2017/03/14)
-
- ANTIFUNGAL 1,2,4-TRIAZOLYL DERIVATIVES HAVING A 5- SULFUR SUBSTITUENT
-
The present invention relates to novel triazole compounds of the formulae (I) and (Il) as defined below, to agricultural and pharmaceutical compositions containing them and to their use as fungicides antiviral and anticancer agents.
- -
-
Page/Page column 117-118
(2010/12/29)
-
- Cyclopropane derivatives
-
The invention provides a process for the preparation of a compound of the general formula (I): STR1 wherein X, Y and R1 to R7 are as defined. In the process, the olefinic analog of the compound of general formula (I) is treated with a halogen-bearing compound in the presence of metallic zinc.
- -
-
-
- α-phenyl- or benzyl-α-cyclopropylalkylene-1H-imidazole- and 1,2,4-triazole-1-ethanols and use against fungus
-
The invention provides novel α-aryl- or -aralkyl-α-(cycloalkyl-alkyl)-1H-azole-1-ethanols, in which the alkyl moiety linking the cycloalkyl group to the ethanol group is substituted or branched at the carbon atom adjacent to the C(OH) group, which are use
- -
-
-