Design and synthesis of aminothiazole modulators of the gamma-secretase enzyme

Bioorg Med Chem Lett. 2016 Aug 15;26(16):3928-37. doi: 10.1016/j.bmcl.2016.07.011.

Kevin D Rynearson ¹, Ronald N Buckle ², Keith D Barnes ², R Jason Herr ², Nicholas J Mayhew ², William D Paquette ², Samuel A Sakwa ², Phuong D Nguyen ¹, Graham Johnson ³, Rudolph E Tanzi ⁴, Steven L Wagner ⁵

Affiliations

1 Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive MC 0624, La Jolla, CA 92093-0624, United States.
2 Department of Medicinal Chemistry, AMRI, East Campus, 3 University Place, Rensselaer, NY 12144, United States.
3 NuPharmAdvise, 3 Lakeside Drive, Sanbornton, NH 03269, United States.
4 Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, United States.
5 Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive MC 0624, La Jolla, CA 92093-0624, United States. Electronic address: slwagner@ucsd.edu.

PMID: 27426299 DOI: 10.1016/j.bmcl.2016.07.011

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 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.

Keywords

Alzheimer’s disease; Aminothiazoles; γ-Secretase modulators.

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