Discovery of tetrahydroindazoles as a novel class of potent and in vivo efficacious gamma secretase modulators

  • Bioorg Med Chem. 2018 Jul 23;26(12):3227-3241. doi: 10.1016/j.bmc.2018.04.053.
Kai Gerlach  1 ,  Scott Hobson  2 ,  Christian Eickmeier  3 ,  Ulrike Groß  4 ,  Clemens Braun  5 ,  Peter Sieger  5 ,  Michel Garneau  5 ,  Stefan Hoerer  4 ,  Niklas Heine  4
Affiliations
  • 1. Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach an der Riss, Germany. Electronic address: [email protected].
  • 2. Central Nervous System Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach an der Riss, Germany.
  • 3. Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach an der Riss, Germany. Electronic address: [email protected].
  • 4. Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach an der Riss, Germany.
  • 5. Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach an der Riss, Germany.
PMID: 29735425 DOI: 10.1016/j.bmc.2018.04.053
Abstract

The identification and optimization of a novel series of centrally efficacious gamma secretase modulators (GSMs) offering an alternative to the privileged aryl imidazole motif is described. Chiral bicyclic tetrahydroindazolyl amine substituted triazolopyridines were identified as structurally distinct novel series of GSMs. Representative compound BI-1408 ((R)-42) was demonstrated to be centrally efficacious in rats at a 30 mg/kg oral dose.

Keywords
Alzheimer’s disease; Aβ42 reduction; Gamma secretase modulators; Tetrahydroindazoles.
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