Design and synthesis of aminothiazole modulators of the gamma-secretase enzyme. Issue 16 (15th August 2016)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 16(2016)
• Page Start: 3928
• Page End: 3937
• Publication Date: 2016-08-15
• Subjects: Alzheimer's disease -- γ-Secretase modulators -- Aminothiazoles; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.07.011
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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 compound1 was conducted in order to align potency with favorable drug-like properties. γ-Secretase modulator28 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 compound28 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.