Discovery and characterization of novel indole and 7-azaindole derivatives as inhibitors of β-amyloid-42 aggregation for the treatment of Alzheimer’s disease

doi:10.1016/j.bmcl.2017.02.001

Bioorganic & Medicinal Chemistry Letters

Volume 27, Issue 6, 15 March 2017, Pages 1405-1411

https://doi.org/10.1016/j.bmcl.2017.02.001 Get rights and content

Abstract

The aggregation of amyloid-β peptides into cytotoxic oligomeric and fibrillary aggregates is believed to be one of the major pathological events in Alzheimer disease. Here we report the design and synthesis of a novel series of indole and 7-azaindole derivatives containing, nitrile, piperidine and N-methyl-piperidine substituents at the 3-position to prevent the pathological self-assembly of amyloid-β. We have further demonstrated that substitution of the azaindole and indole derivatives at the 3 positions is required to obtain compounds with improved physicochemical properties to allow brain penetration.

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References (33)

M.A. Smith
Int Rev Neurobiol
(1998)
R. Vassar
Adv Drug Deliv Rev
(2002)
T. Tomiyama et al.
J Biol Chem
(1996)
S.J. Wood et al.
J Biol Chem
(1996)
C. Ballatore et al.
Bioorg Med Chem
(2012)
B. Bulic et al.
Neuropharmacology
(2010)
R.A. Cherny et al.
Neuron
(2001)
D.G. Flood et al.
Neurobiol Aging
(2002)
P. Rzepecki et al.
J Biol Chem
(2004)
H. Kroth et al.
J Biol Chem
(2012)

H. Kroth et al.

Bioorg Med Chem Lett

(2016)

D.J. Selkoe

J Neuropathol Exp Neurol

(1994)

C.M. Clark et al.

Ann Intern Med

(2003)

S.L. Rogers et al.

Arch Intern Med

(1998)

M. Sabbagh et al.

BMC. Neurol.

(2011)

R. Vassar et al.

J Neurosci

(2009)

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Discovery and characterization of novel indole and 7-azaindole derivatives as inhibitors of β-amyloid-42 aggregation for the treatment of Alzheimer’s disease

Abstract

Graphical abstract

Int Rev Neurobiol

Adv Drug Deliv Rev

J Biol Chem

J Biol Chem

Bioorg Med Chem

Neuropharmacology

Neuron

Neurobiol Aging

J Biol Chem

J Biol Chem

Bioorg Med Chem Lett

J Neuropathol Exp Neurol

Ann Intern Med

Arch Intern Med

BMC. Neurol.

J Neurosci