1353570-14-5Relevant articles and documents
Design and synthesis of aminothiazole modulators of the gamma-secretase enzyme
Rynearson, Kevin D.,Buckle, Ronald N.,Barnes, Keith D.,Herr, R. Jason,Mayhew, Nicholas J.,Paquette, William D.,Sakwa, Samuel A.,Nguyen, Phuong D.,Johnson, Graham,Tanzi, Rudolph E.,Wagner, Steven L.
, p. 3928 - 3937 (2016)
The design and construction of a series of novel aminothiazole-derived γ-secretase modulators is described. The incorporation of heterocyclic replacements of the terminal phenyl D-ring of lead compound 1 was conducted in order to align potency with favorable drug-like properties. γ-Secretase modulator 28 displayed good activity for in vitro inhibition of Aβ42, as well as substantial improvement in ADME and physicochemical properties, including aqueous solubility. Pharmacokinetic evaluation of compound 28 in mice revealed good brain penetration, as well as good clearance, half-life, and volume of distribution which collectively support the continued development of this class of compounds.
Design and synthesis of novel methoxypyridine-derived gamma-secretase modulators
Barnes, Keith D.,Buckle, Ronald N.,Chen, Xinchao,Herr, R. Jason,Johnson, Graham,Lin, Juinn H.,Mayhew, Nicholas J.,Mobley, William C.,Nguyen, Phuong,Paquette, William D.,Rynearson, Kevin D.,Sakwa, Samuel A.,Tanzi, Rudolph E.,Wagner, Steven L.,Yang, Jinhai
, (2020/09/22)
The evolution of gamma-secretase modulators (GSMs) through the introduction of novel heterocycles with the goal of aligning activity for reducing the levels of Aβ42 and properties consistent with a drug-like molecule are described. The insertion of a methoxypyridine motif within the tetracyclic scaffold provided compounds with improved activity for arresting Aβ42 production as well as improved properties, including solubility. In vivo pharmacokinetic analysis demonstrated that several compounds within the novel series were capable of crossing the BBB and accessing the therapeutic target. Treatment with methoxypyridine-derived compound 64 reduced Aβ42 levels in the plasma of J20 mice, in addition to reducing Aβ42 levels in the plasma and brain of Tg2576 mice.
COMPOUNDS AND USES THEREOF IN MODULATING LEVELS OF VARIOUS AMYLOID BETA PEPTIDE ALLOFORMS
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Page/Page column 71, (2012/01/14)
The invention provides a novel compound having a structure corresponding to Formula (I): (A)-(B)-(C)-(D) or a pharmaceutically acceptable salt or prodrug thereof and methods for using them.
