Potent benzoazepinone γ-secretase modulators with improved bioavailability

Bioorg Med Chem Lett. 2015 Sep 1;25(17):3495-500. doi: 10.1016/j.bmcl.2015.06.032.

Joey L Methot ¹, Christian Fischer ², Chaomin Li ², Alexey Rivkin ², Sean P Ahearn ², William Colby Brown ², Sam Kattar ², Elizabeth Kelley ², Dawn M Mampreian ², Adam Schell ², Andrew Rosenau ², Hua Zhou ², Richard Ball ², Sujal V Deshmukh ², Valentina V Jeliazkova-Mecheva ², Damaris Diaz ², Lily Y Moy ², Candia M Kenific ², Chris Moxham ², Sanjiv Shah ², Hugh Nuthall ², Alexander A Szewczak ², Armetta Hill ², Bethany Hughes ², Nadya Smotrov ², Benito Munoz ², Thomas A Miller ², Mark S Shearman ²

Affiliations

1 Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: joey_methot@merck.com.
2 Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.

PMID: 26142947 DOI: 10.1016/j.bmcl.2015.06.032

Abstract

The triazolyl amide γ-secretase modulators are potent alternatives to the cinnamyl amides that have entered the clinic for the treatment of Alzheimer's disease. Herein we build on the lead benzoazepinones described in our prior communication with imidazomethoxyarene moiety alternatives that offer opportunities to fine tune physical properties as well as address hERG binding and PK. Both half-life and bioavailability were significantly improved, especially in dog, with robust brain Aβ42 lowering maintained in both transgenic mouse and rat.

Keywords

Bioavailability; Pharmacokinetics; γ-Secretase modulator.

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