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γ-Secretase Modulation and its Promise for Alzheimers Disease: a Medicinal Chemistry Perspective

[ Vol. 8 , Issue. 1 ]

Author(s):

Ilaria Peretto and Elena La Porta   Pages 38 - 46 ( 9 )

Abstract:


γ-Secretase modulation holds the promise for the development of a disease-modifying therapy for Alzheimers disease (AD). This novel concept of manipulating the cleavage specificity of the γ-secretase enzyme by pharmacological means implies that steady state levels of the potentially disease-causing amyloid-β(1-42) peptide can be lowered without the undesired side effects associated with full inhibition of this aspartyl-type protease. Following on from the initial discovery that certain non-steroidal anti-inflammatory drugs (NSAIDs) exhibit properties characteristic of γ-secretase modulators, this class of compounds has been extensively studied and exploited, leading to the discovery of NSAIDs derivatives endowed with improved potency for the reduction of amyloid-β(1-42) peptide production. In addition, a very limited number of non-NSAID derived γ-secretase modulators has also been recently claimed in the patent literature, suggesting that only a restricted number of pharmacophores might be involved in the modulation of γ-secretase.

, γ-Secretase, Modulation, and, its, Promise, for, Alzheimers, Disease:, a, Medicinal, Chemistry, Perspective

Affiliation:

NiKem Research SrL, Department of Medicinal Chemistry, via Zambeletti 25, 20021 Baranzate (Milan), Italy.



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