Triazolopyrimidinones as γ-secretase modulators: structure–activity relationship, modulator profile, and in vivo profiling

Ulrika Yngve; Kim Paulsen; Istvan Macsari; Marie Sundström; Ellen Santangelo; Christian Linde; Krisztian Bogar; Fredrik Lake; Yevgeni Besidski; Jonas Malmborg; Kia Strömberg; Paulina Appelkvist; Ann-Cathrine Radesäter; Fredrik Olsson; Daniel Bergström; Rebecka Klintenberg; Per I. Arvidsson

doi:10.1039/C2MD20312J

Triazolopyrimidinones as γ-secretase modulators: structure–activity relationship, modulator profile, and in vivo profiling†‡

Ulrika Yngve,*^a Kim Paulsen,^a Istvan Macsari,^a Marie Sundström,^a Ellen Santangelo,^a Christian Linde,^a Krisztian Bogar,^a Fredrik Lake,^a Yevgeni Besidski,^a Jonas Malmborg,^b Kia Strömberg,^cd Paulina Appelkvist,^c Ann-Cathrine Radesäter,^c Fredrik Olsson,^c Daniel Bergström,^c Rebecka Klintenberg^c and Per I. Arvidsson^efg

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* Corresponding authors

^a Medicinal Chemistry, CNSP iMed Science, AstraZeneca R&D, Innovative Medicines, SE-15185 Södertälje, Sweden
E-mail: ulrikayngve@telia.com
Tel: +46-70-3095769

^b DMPK, CNSP iMed Science, AstraZeneca R&D, Innovative Medicines, SE-15185 Södertälje, Sweden

^c Neuroscience, CNSP iMed Science, AstraZeneca R&D, Innovative Medicines, SE-15185 Södertälje, Sweden

^d Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

^e CNSP iMed Project Management, AstraZeneca R&D, Innovative Medicines, SE-15185 Södertälje, Sweden

^f Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Centre, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden

^g School of Pharmacy and Pharmacology, University of KwaZulu-Natal, Westville Campus, Private Bag X54001, Durban 4000, South Africa

Abstract

The structure–activity relationship for a series of potent γ-secretase modulators based on the 6,7-dihydro-4H-[1,2,4]triazolo[1,5-a]pyrimidin-5-one scaffold is described. Furthermore, we report details regarding the modulator profile on Aβ processing, as well as in vivo efficacy, for the optimized compounds.

MedChemComm

Triazolopyrimidinones as γ-secretase modulators: structure–activity relationship, modulator profile, and in vivo profiling†‡

Abstract

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Triazolopyrimidinones as γ-secretase modulators: structure–activity relationship, modulator profile, and in vivo profiling

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