2. Academic Validation
  3. Generation of Leads for γ-Secretase Modulation

Generation of Leads for γ-Secretase Modulation

  • J Med Chem. 2020 Aug 13;63(15):8216-8230. doi: 10.1021/acs.jmedchem.0c00446.
Mihirbaran Mandal 1,  Alexei Buevich 2,  John P Caldwell 1,  Lynn Hyde 3,  Xianhai Huang 1,  Xiaoxiang Liu 1,  Brian McKittrick 1,  Robert D Mazzola 1,  Dmitri Pissarnitski 1,  Anandan Palani 1,  Lili Zhang 3,  Eric Parker 3,  Li Xiao 4,  Diane Rindgen 5,  Zhaoning Zhu 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • 2 Department of NMR Structure Elucidation, Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • 3 Department of Neuroscience, Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • 4 Department of Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • 5 Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
PMID: 32786237 DOI: 10.1021/acs.jmedchem.0c00446
Abstract

Herein, we disclose three structurally differentiated γ-secretase modulators (GSMs) based on an oxadiazine scaffold. The analogues from series I potently inhibit the generation of Aβ42 in vitro when the substituents at 3 and 4 positions of the oxadiazine moiety adopt an α orientation (cf. 11). To address the concern around potential reactivity of the exocyclic double bond present in series I toward nucleophilic attack, compounds containing either an endocyclic double bond, such as 20 (series II), or devoid of an olefinic moiety, such as 27 (series III), were designed and validated as novel GSMs. Compound 11 and azepine 20 exhibit robust lowering of CSF Aβ42 in rats treated with a 30 mg/kg oral dose.

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