Discovery of tetrahydroindazoles as a novel class of potent and in vivo efficacious gamma secretase modulators. Issue 12 (23rd July 2018)

• Record Type: Journal Article
• Authors: Gerlach, Kai; Hobson, Scott; Eickmeier, Christian; Groß, Ulrike; Braun, Clemens; Sieger, Peter; Garneau, Michel; Hoerer, Stefan; Heine, Niklas
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 12(2018)
• Page Start: 3227
• Page End: 3241
• Publication Date: 2018-07-23
• Subjects: AD Alzheimer's disease -- Aβ amyloid β peptide -- APP amyloid precursor protein -- BACE1 β-amyloid cleavage enzyme 1, β-secretase 1 -- GSM gamma secretase modulator -- LHS left hand side -- NSAID non-steroidal anti-inflammatory drug -- SAR structure activity relationships -- HLM human liver microsomes -- RLM rat liver microsomes -- PPB plasma protein binding, MDCK cells, Madin-Darby canine kidney epithelial cells -- pgp p-glycoprotein -- MDR1 multidrug resistance protein 1 -- MRT mean residence time -- psi pounds per square inch; Gamma secretase modulators -- Tetrahydroindazoles -- Alzheimer's disease -- Aβ42 reduction; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.04.053
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.